@article{Aqvist1994,
author = {\AA qvist, J and Medina, C and Samuelsson, JE},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/10\_E\_01\_ProtEng7\_385\_Aqvist.pdf:pdf},
journal = {Protein engineering},
pages = {385--391},
title = {{A new method for predicting binding affinity in computer-aided drug design}},
url = {http://peds.oxfordjournals.org/content/7/3/385.short},
volume = {7},
year = {1994}
}
@article{Ryde1995,
author = {Ryde, U},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/340210106\_ftp.pdf:pdf},
journal = {Proteins: Structure, Function, and Bioinformatics},
keywords = {bond length con-,coordination,effective,five-,force-field,four-coordination,ligand exchange,reaction mechanism,zinc parameterization},
pages = {40--56},
title = {{Molecular dynamics simulations of alcohol dehydrogenase with a four‐or five‐coordinate catalytic zinc ion}},
url = {http://onlinelibrary.wiley.com/doi/10.1002/prot.340210106/abstract},
volume = {56},
year = {1995}
}
@article{Jorgensen1996,
author = {Jorgensen, WL and Maxwell, DS and Tirado-Rives, J},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/OPLS-AA\_1996.pdf:pdf},
journal = {Journal of the American Chemical Society},
number = {15},
pages = {11225--11236},
title = {{Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids}},
url = {http://pubs.acs.org/doi/abs/10.1021/ja9621760},
volume = {7863},
year = {1996}
}
@article{Ryde1996,
abstract = {The coordination number of the catalytic zinc ion in alcohol dehydrogenase has been studied by integrated ab initio quantum-chemical and molecular mechanics geometry optimisations involving the whole enzyme. A four-coordinate active-site zinc ion is 100-200 kJ/mol more stable than a five-coordinate one, depending on the ligands. The only stable binding site for a fifth ligand at the zinc ion is opposite to the normal substrate site, in a small cavity buried behind the zinc ion. The zinc coordination sphere has to be strongly distorted to accommodate a ligand in this site, and the ligand makes awkward contacts with surrounding atoms. Thus, the results do not support proposals attributing an important role to five-coordinate zinc complexes in the catalytic mechanism of alcohol dehydrogenase. The present approach makes it possible also to quantify the strain induced by the enzyme onto the zinc ion and its ligands; it amounts to 42-87 kJ/mol for four-coordinate active-site zinc ion complexes and 131-172 kJ/mol for five-coordinate ones. The four-coordinate structure with a water molecule bound to the zinc ion is about 20 kJ/mol less strained than the corresponding structure with a hydroxide ion, indicating that the enzyme does not speed up the reaction by forcing the zinc coordination sphere into a structure similar to the reaction intermediates.},
author = {Ryde, U},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/Marquez\_G\_paper.pdf:pdf},
issn = {0920-654X},
journal = {Journal of computer-aided molecular design},
keywords = {Alcohol Dehydrogenase,Alcohol Dehydrogenase: chemistry,Alcohol Dehydrogenase: metabolism,Amino Acid Sequence,Binding Sites,Calorimetry,Ligands,Models, Chemical,Models, Molecular,Molecular Sequence Data,Protein Conformation,Quantum Theory,Software,Zinc,Zinc: analysis,Zinc: chemistry},
month = apr,
number = {2},
pages = {153--64},
pmid = {8741019},
title = {{The coordination of the catalytic zinc in alcohol dehydrogenase studied by combined quantum-chemical and molecular mechanics calculations.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/8741019},
volume = {10},
year = {1996}
}
@article{Hansson1998,
abstract = {A recent method for estimating ligand binding affinities is extended. This method employs averages of interaction potential energy terms from molecular dynamics simulations or other thermal conformational sampling techniques. Incorporation of systematic deviations from electrostatic linear response, derived from free energy perturbation studies, into the absolute binding free energy expression significantly enhances the accuracy of the approach. This type of method may be useful for computational prediction of ligand binding strengths, e.g., in drug design applications.},
author = {Hansson, T and Marelius, J and Aqvist, J},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/Ligand binding affinity prediction by LIE.pdf:pdf},
issn = {0920-654X},
journal = {Journal of computer-aided molecular design},
keywords = {Binding Sites,Computer Simulation,Drug Design,Kinetics,Ligands,Models, Chemical,Proteins,Proteins: chemistry,Proteins: metabolism,Static Electricity,Thermodynamics},
month = jan,
number = {1},
pages = {27--35},
pmid = {9570087},
title = {{Ligand binding affinity prediction by linear interaction energy methods.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/9570087},
volume = {12},
year = {1998}
}
@article{SantaLucia1998,
author = {SantaLucia, J},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/PNAS-1998-SantaLucia-1460-5.pdf:pdf},
journal = {Proceedings of the National Academy of \ldots},
number = {February},
pages = {1460--1465},
title = {{A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics}},
url = {http://www.pnas.org/content/95/4/1460.short},
volume = {95},
year = {1998}
}
@article{Kollman2000,
abstract = {A historical perspective on the application of molecular dynamics (MD) to biological macromolecules is presented. Recent developments combining state-of-the-art force fields with continuum solvation calculations have allowed us to reach the fourth era of MD applications in which one can often derive both accurate structure and accurate relative free energies from molecular dynamics trajectories. We illustrate such applications on nucleic acid duplexes, RNA hairpins, protein folding trajectories, and protein-ligand, protein-protein, and protein-nucleic acid interactions.},
author = {Kollman, P a and Massova, I and Reyes, C and Kuhn, B and Huo, S and Chong, L and Lee, M and Lee, T and Duan, Y and Wang, W and Donini, O and Cieplak, P and Srinivasan, J and Case, D a and Cheatham, T E},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ar000033j.pdf:pdf},
issn = {0001-4842},
journal = {Accounts of chemical research},
keywords = {Base Sequence,DNA,DNA: chemistry,Models, Molecular,Molecular Structure,Proteins,Proteins: chemistry,RNA,RNA: chemistry,Thermodynamics},
month = dec,
number = {12},
pages = {889--97},
pmid = {11123888},
title = {{Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/11123888},
volume = {33},
year = {2000}
}
@article{Andricioaei2001,
author = {Andricioaei, Ioan and Karplus, Martin},
doi = {10.1063/1.1401821},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/JChemPhys\_115\_6289.pdf:pdf},
issn = {00219606},
journal = {The Journal of Chemical Physics},
number = {14},
pages = {6289},
title = {{On the calculation of entropy from covariance matrices of the atomic fluctuations}},
url = {http://link.aip.org/link/JCPSA6/v115/i14/p6289/s1\&Agg=doi},
volume = {115},
year = {2001}
}
@article{Aqvist2001,
author = {Aqvist, J and Marelius, John},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/The Linear Interaction Energy Method for Predicting Ligand B.pdf:pdf},
journal = {Combinatorial chemistry \& high \ldots},
pages = {613--626},
title = {{The linear interaction energy method for predicting ligand binding free energies}},
url = {http://www.ingentaconnect.com/content/ben/cchts/2001/00000004/00000008/art00003},
year = {2001}
}
@article{Wang2001,
author = {Wang, J and Morin, Paul and Wang, W and Kollman, Peter A},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/HIV\_RT.pdf:pdf},
journal = {Journal of the American Chemical Society},
number = {8},
pages = {5221--5230},
title = {{Use of MM-PBSA in reproducing the binding free energies to HIV-1 RT of TIBO derivatives and predicting the binding mode to HIV-1 RT of efavirenz by docking and MM-PBSA}},
url = {http://pubs.acs.org/doi/abs/10.1021/ja003834q},
volume = {123},
year = {2001}
}
@article{Aqvist2002,
abstract = {Simplified free energy calculations based on force field energy estimates of ligand-receptor interactions and thermal conformational sampling have emerged as a useful tool in structure-based ligand design. Here we give an overview of the linear interaction energy (LIE) method for calculating ligand binding free energies from molecular dynamics simulations. A notable feature is that the binding energetics can be predicted by considering only the intermolecular interactions of the ligand in the associated and dissociated states. The approximations behind this approach are examined, and different parametrizations of the model are discussed. LIE-type methods appear particularly promising for computational "lead optimization". Recent applications to protein-protein interactions and ion channel blocking are also discussed.},
author = {Aqvist, Johan and Luzhkov, Victor B and Brandsdal, Bj\o rn O},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ar010014p.pdf:pdf},
issn = {0001-4842},
journal = {Accounts of chemical research},
keywords = {Animals,Computer Simulation,Humans,Ligands,Motion,Protein Binding,Proteins,Proteins: chemistry,Thermodynamics},
month = jun,
number = {6},
pages = {358--65},
pmid = {12069620},
title = {{Ligand binding affinities from MD simulations.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12069620},
volume = {35},
year = {2002}
}
@article{Fogolari2002,
abstract = {Electrostatics plays a fundamental role in virtually all processes involving biomolecules in solution. The Poisson-Boltzmann equation constitutes one of the most fundamental approaches to treat electrostatic effects in solution. The theoretical basis of the Poisson-Boltzmann equation is reviewed and a wide range of applications is presented, including the computation of the electrostatic potential at the solvent-accessible molecular surface, the computation of encounter rates between molecules in solution, the computation of the free energy of association and its salt dependence, the study of pKa shifts and the combination with classical molecular mechanics and dynamics. Theoretical results may be used for rationalizing or predicting experimental results, or for suggesting working hypotheses. An ever-increasing body of successful applications proves that the Poisson-Boltzmann equation is a useful tool for structural biology and complementary to other established experimental and theoretical methodologies.},
author = {Fogolari, F and Brigo, a and Molinari, H},
doi = {10.1002/jmr.577},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/Fogolari2002.pdf:pdf},
issn = {0952-3499},
journal = {Journal of molecular recognition : JMR},
keywords = {Algorithms,Animals,Computer Simulation,Humans,Macromolecular Substances,Poisson Distribution,Static Electricity,Thermodynamics},
number = {6},
pages = {377--92},
pmid = {12501158},
title = {{The Poisson-Boltzmann equation for biomolecular electrostatics: a tool for structural biology.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/12501158},
volume = {15},
year = {2002}
}
@article{Jacobson2002,
author = {Jacobson, Matthew P. and Kaminski, George a. and Friesner, Richard a. and Rapp, Chaya S.},
doi = {10.1021/jp021564n},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/PLOP.pdf:pdf},
issn = {1520-6106},
journal = {The Journal of Physical Chemistry B},
month = nov,
number = {44},
pages = {11673--11680},
title = {{Force Field Validation Using Protein Side Chain Prediction}},
url = {http://pubs.acs.org/doi/abs/10.1021/jp021564n},
volume = {106},
year = {2002}
}
@article{Walker2002,
author = {Walker, Ross C. and de Souza, Melanie M. and Mercer, Ian P. and Gould, Ian R. and Klug, David R.},
doi = {10.1021/jp0261814},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jp0261814.pdf:pdf},
issn = {1520-6106},
journal = {The Journal of Physical Chemistry B},
month = nov,
number = {44},
pages = {11658--11665},
title = {{Large and Fast Relaxations inside a Protein:  Calculation and Measurement of Reorganization Energies in Alcohol Dehydrogenase}},
url = {http://pubs.acs.org/doi/abs/10.1021/jp0261814},
volume = {106},
year = {2002}
}
@article{Jackson2003,
abstract = {Silent information regulator 2 (Sir2) enzymes catalyze NAD+-dependent protein/histone deacetylation, where the acetyl group from the lysine epsilon-amino group is transferred to the ADP-ribose moiety of NAD+, producing nicotinamide and the novel metabolite O-acetyl-ADP-ribose. Sir2 proteins have been shown to regulate gene silencing, metabolic enzymes, and life span. Recently, nicotinamide has been implicated as a direct negative regulator of cellular Sir2 function; however, the mechanism of nicotinamide inhibition was not established. Sir2 enzymes are multifunctional in that the deacetylase reaction involves the cleavage of the nicotinamide-ribosyl, cleavage of an amide bond, and transfer of the acetyl group ultimately to the 2'-ribose hydroxyl of ADP-ribose. Here we demonstrate that nicotinamide inhibition is the result of nicotinamide intercepting an ADP-ribosyl-enzyme-acetyl peptide intermediate with regeneration of NAD+ (transglycosidation). The cellular implications are discussed. A variety of 3-substituted pyridines was found to be substrates for enzyme-catalyzed transglycosidation. A Br\"{o}nsted plot of the data yielded a slope of +0.98, consistent with the development of a nearly full positive charge in the transition state, and with basicity of the attacking nucleophile as a strong predictor of reactivity. NAD+ analogues including beta-2'-deoxy-2'-fluororibo-NAD+ and a His-to-Ala mutant were used to probe the mechanism of nicotinamide-ribosyl cleavage and acetyl group transfer. We demonstrate that nicotinamide-ribosyl cleavage is distinct from acetyl group transfer to the 2'-OH ribose. The observed enzyme-catalyzed formation of a labile 1'-acetylated-ADP-fluororibose intermediate using beta-2'-deoxy-2'-fluororibo-NAD+ supports a mechanism where, after nicotinamide-ribosyl cleavage, the carbonyl oxygen of acetylated substrate attacks the C-1' ribose to form an initial iminium adduct.},
author = {Jackson, Michael D and Schmidt, Manning T and Oppenheimer, Norman J and Denu, John M},
doi = {10.1074/jbc.M306552200},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/J. Biol. Chem.-2003-Jackson-50985-98.pdf:pdf},
isbn = {5098550998},
issn = {0021-9258},
journal = {The Journal of biological chemistry},
keywords = {Amino Acid Substitution,Catalysis,Glycosylation,Histone Deacetylases,Histone Deacetylases: genetics,Histone Deacetylases: physiology,Humans,Kinetics,Models, Chemical,NAD,NAD: chemistry,Niacinamide,Niacinamide: antagonists \& inhibitors,Pyridines,Pyridines: chemistry,Ribose,Ribose: chemistry,Silent Information Regulator Proteins, Saccharomyces cerevisiae,Silent Information Regulator Proteins, Saccharomyces cerevisiae: genetics,Silent Information Regulator Proteins, Saccharomyces cerevisiae: physiology,Sirtuin 1,Sirtuin 2,Sirtuins,Sirtuins: genetics,Sirtuins: physiology},
month = dec,
number = {51},
pages = {50985--98},
pmid = {14522996},
title = {{Mechanism of nicotinamide inhibition and transglycosidation by Sir2 histone/protein deacetylases.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/14522996},
volume = {278},
year = {2003}
}
@article{Sauve2003,
author = {Sauve, AA and Schramm, VL},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/bi034959l.pdf:pdf},
journal = {Biochemistry},
number = {31},
title = {{Sir2 regulation by nicotinamide results from switching between base exchange and deacetylation chemistry}},
url = {http://pubs.acs.org/doi/abs/10.1021/bi034959l},
volume = {42},
year = {2003}
}
@article{Friesner2004,
abstract = {Unlike other methods for docking ligands to the rigid 3D structure of a known protein receptor, Glide approximates a complete systematic search of the conformational, orientational, and positional space of the docked ligand. In this search, an initial rough positioning and scoring phase that dramatically narrows the search space is followed by torsionally flexible energy optimization on an OPLS-AA nonbonded potential grid for a few hundred surviving candidate poses. The very best candidates are further refined via a Monte Carlo sampling of pose conformation; in some cases, this is crucial to obtaining an accurate docked pose. Selection of the best docked pose uses a model energy function that combines empirical and force-field-based terms. Docking accuracy is assessed by redocking ligands from 282 cocrystallized PDB complexes starting from conformationally optimized ligand geometries that bear no memory of the correctly docked pose. Errors in geometry for the top-ranked pose are less than 1 \AA in nearly half of the cases and are greater than 2 \AA in only about one-third of them. Comparisons to published data on rms deviations show that Glide is nearly twice as accurate as GOLD and more than twice as accurate as FlexX for ligands having up to 20 rotatable bonds. Glide is also found to be more accurate than the recently described Surflex method.},
author = {Friesner, R a and Banks, J L and Murphy, R B and Halgren, T a and Klicic, J J and Mainz, D T and Repasky, M P and Knoll, E H and Shelley, M and Perry, J K and Shaw, D E and Francis, P and Shenkin, P S},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm0306430.pdf:pdf},
journal = {Journal of Medicinal Chemistry},
keywords = {accuracy,analytic method,article,binding sites,computer program,drug design,energy,ligand,ligands,models,molecular,molecular conformation,molecular structure,monte carlo method,protein,protein conformation,proteins,quantitative structure activity relationship,thermodynamics,thymidine kinase},
number = {7},
pages = {1739--1749},
title = {{Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy}},
volume = {47},
year = {2004}
}
@article{Kontoyianni2004,
author = {Kontoyianni, Maria},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm0302997.pdf:pdf},
journal = {Journal of Medicinal Chemistry},
pages = {558--565},
title = {{Evaluation of docking performance: comparative data on docking algorithms}},
url = {http://pubs.acs.org/doi/abs/10.1021/jm0302997},
volume = {47},
year = {2004}
}
@article{Avalos2005,
abstract = {Sir2 enzymes form a unique class of NAD(+)-dependent deacetylases required for diverse biological processes, including transcriptional silencing, regulation of apoptosis, fat mobilization, and lifespan regulation. Sir2 activity is regulated by nicotinamide, a noncompetitive inhibitor that promotes a base-exchange reaction at the expense of deacetylation. To elucidate the mechanism of nicotinamide inhibition, we determined ternary complex structures of Sir2 enzymes containing nicotinamide. The structures show that free nicotinamide binds in a conserved pocket that participates in NAD(+) binding and catalysis. Based on our structures, we engineered a mutant that deacetylates peptides by using nicotinic acid adenine dinucleotide (NAAD) as a cosubstrate and is inhibited by nicotinic acid. The characteristics of the altered specificity enzyme establish that Sir2 enzymes contain a single site that participates in catalysis and nicotinamide regulation and provides additional insights into the Sir2 catalytic mechanism.},
author = {Avalos, Jos\'{e} L and Bever, Katherine M and Wolberger, Cynthia},
doi = {10.1016/j.molcel.2005.02.022},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1-s2.0-S1097276505011214-main.pdf:pdf},
issn = {1097-2765},
journal = {Molecular cell},
keywords = {Acetylation,Amino Acid Sequence,Catalysis,Gene Expression Regulation, Fungal,Histone Deacetylases,Histone Deacetylases: genetics,Histone Deacetylases: metabolism,Molecular Sequence Data,NAD,NAD: analogs \& derivatives,NAD: metabolism,Niacin,Niacin: pharmacology,Niacinamide,Niacinamide: metabolism,Sequence Homology, Amino Acid,Silent Information Regulator Proteins, Saccharomyc,Sirtuin 2,Sirtuins,Sirtuins: chemistry,Sirtuins: genetics,Sirtuins: metabolism,Substrate Specificity,Vasodilator Agents,Vasodilator Agents: pharmacology},
month = mar,
number = {6},
pages = {855--68},
pmid = {15780941},
title = {{Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15780941},
volume = {17},
year = {2005}
}
@article{Kuhn2005,
abstract = {The MM-PBSA approach has become a popular method for calculating binding affinities of biomolecular complexes. Published application examples focus on small test sets and few proteins and, hence, are of limited relevance in assessing the general validity of this method. To further characterize MM-PBSA, we report on a more extensive study involving a large number of ligands and eight different proteins. Our results show that applying the MM-PBSA energy function to a single, relaxed complex structure is an adequate and sometimes more accurate approach than the standard free energy averaging over molecular dynamics snapshots. The use of MM-PBSA on a single structure is shown to be valuable (a) as a postdocking filter in further enriching virtual screening results, (b) as a helpful tool to prioritize de novo design solutions, and (c) for distinguishing between good and weak binders (DeltapIC(50) > or = 2-3), but rarely to reproduce smaller free energy differences.},
author = {Kuhn, Bernd and Gerber, Paul and Schulz-Gasch, Tanja and Stahl, Martin},
doi = {10.1021/jm049081q},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm049081q.pdf:pdf},
issn = {0022-2623},
journal = {Journal of medicinal chemistry},
keywords = {Binding Sites,Drug Design,Ligands,Molecular Structure,Protein Binding,Proteins,Proteins: chemistry,Quantitative Structure-Activity Relationship,Solvents,Solvents: chemistry,Thermodynamics},
month = jun,
number = {12},
pages = {4040--8},
pmid = {15943477},
title = {{Validation and use of the MM-PBSA approach for drug discovery.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/15943477},
volume = {48},
year = {2005}
}
@article{Napper2005,
author = {Napper, AD and Hixon, Jeffrey},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm050522v.pdf:pdf},
journal = {Journal of Medicinal Chemistry},
pages = {8045--8054},
title = {{Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1}},
url = {http://pubs.acs.org/doi/abs/10.1021/jm050522v},
volume = {48},
year = {2005}
}
@article{Alonso2006,
abstract = {A rational approach is needed to maximize the chances of finding new drugs, and to exploit the opportunities of potential new drug targets emerging from genomic and proteomic initiatives, and from the large libraries of small compounds now readily available through combinatorial chemistry. Despite a shaky early history, computer-aided drug design techniques can now be effective in reducing costs and speeding up drug discovery. This happy outcome results from development of more accurate and reliable algorithms, use of more thoughtfully planned strategies to apply them, and greatly increased computer power to allow studies with the necessary reliability to be performed. Our review focuses on applications and protocols, with the main emphasis on critical analysis of recent studies where docking calculations and molecular dynamics (MD) simulations were combined to dock small molecules into protein receptors. We highlight successes to demonstrate what is possible now, but also point out drawbacks and future directions. The review is structured to lead the reader from the simpler to more compute-intensive methods. Thus, while inexpensive and fast docking algorithms can be used to scan large compound libraries and reduce their size, more accurate but expensive MD simulations can be applied when a few selected ligand candidates remain. MD simulations can be used: during the preparation of the protein receptor before docking, to optimize its structure and account for protein flexibility; for the refinement of docked complexes, to include solvent effects and account for induced fit; to calculate binding free energies, to provide an accurate ranking of the potential ligands; and in the latest developments, during the docking process itself to find the binding site and correctly dock the ligand a priori.},
author = {Alonso, Hern\'{a}n and Bliznyuk, Andrey a and Gready, Jill E},
doi = {10.1002/med.20067},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/mdy\_md\_docking\_alonso.pdf:pdf},
issn = {0198-6325},
journal = {Medicinal research reviews},
keywords = {Computer Simulation,Drug Design,Ligands,Models, Molecular,Protein Conformation,Thermodynamics},
month = sep,
number = {5},
pages = {531--68},
pmid = {16758486},
title = {{Combining docking and molecular dynamic simulations in drug design.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16758486},
volume = {26},
year = {2006}
}
@article{Baron2006,
abstract = {During the past decades, the calculation of accurate free-energy differences from molecular simulations has become feasible in practice. In contrast, the reliable estimation of absolute entropies and entropy differences from these simulations is a notoriously difficult problem. This article investigates critically the method to estimate configurational entropies from molecular dynamics simulations based on the quasi-harmonic approximation. The theory, assumptions, and approximations underlying this method are presented, as well as its connection with essential- mode and normal-mode analyses. In particular, the following points are considered: (i) the relationship between quasi-harmonic and essential modes; (ii) the requirement of mass-weighting (or metric- tensor-weighting) in quasi-harmonic analysis; (iii) the effect of anharmonicities in the individual modes on the estimated entropy; (iv) the effect of pairwise (supralinear) correlations among the different modes on the estimated entropy. The analyses are carried out in the context of long (hundreds of nanoseconds) molecular dynamics simulations involving the reversible folding of $\beta$- peptides, considering individually the specific properties of the folded and unfolded ensembles. The anharmonicity correction to the quasi- harmonic entropy is small. In contrast, the pairwise (supralinear) correlation correction is},
author = {Baron, Riccardo and Gunsteren, Wilfred F Van and H\"{u}nenberger, Philippe H},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/TPC\_11\_2006.pdf:pdf},
journal = {Trends in Physical Chemistry},
keywords = {anharmonicity,computer simulation,correlation,entropy,quasi harmonic analysis},
pages = {87--122},
title = {{Estimating the configurational entropy from molecular dynamics simulations: Anharmonicity and correlation corrections to the quasi-harmonic approximation}},
url = {http://mccammon.ucsd.edu/~rbaron/TPC\_11\_2006.pdf},
volume = {11},
year = {2006}
}
@article{Hoff2006,
abstract = {Sirtuin proteins comprise a unique class of NAD+-dependent protein deacetylases. Although several structures of sirtuins have been determined, the mechanism by which NAD+ cleavage occurs has remained unclear. We report the structures of ternary complexes containing NAD+ and acetylated peptide bound to the bacterial sirtuin Sir2Tm and to a catalytic mutant (Sir2Tm(H116Y)). NAD+ in these structures binds in a conformation different from that seen in previous structures, exposing the alpha face of the nicotinamide ribose to the carbonyl oxygen of the acetyl lysine substrate. The NAD+ conformation is identical in both structures, suggesting that proper coenzyme orientation is not dependent on contacts with the catalytic histidine. We also present the structure of Sir2Tm(H116A) bound to deacteylated peptide and 3'-O-acetyl ADP ribose. Taken together, these structures suggest a mechanism for nicotinamide cleavage in which an invariant phenylalanine plays a central role in promoting formation of the O-alkylamidate reaction intermediate and preventing nicotinamide exchange.},
author = {Hoff, KG and Avalos, JL and Sens, Kristin and Wolberger, Cynthia},
doi = {10.1016/j.str.2006.06.006},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1-s2.0-S0969212606002899-main.pdf:pdf},
issn = {0969-2126},
journal = {Structure},
keywords = {Crystallization,Crystallography,Models,Molecular,Multiprotein Complexes,Multiprotein Complexes: chemistry,NAD,NAD: chemistry,NAD: metabolism,O-Acetyl-ADP-Ribose,O-Acetyl-ADP-Ribose: chemistry,O-Acetyl-ADP-Ribose: metabolism,Peptides,Peptides: chemistry,Peptides: metabolism,Sirtuins,Sirtuins: chemistry,Sirtuins: metabolism,X-Ray},
month = aug,
number = {8},
pages = {1231--40},
pmid = {16905097},
title = {{Insights into the Sirtuin Mechanism from Ternary Complexes Containing NAD+ and Acetylated Peptide}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16905097 http://www.sciencedirect.com/science/article/pii/S0969212606002899},
volume = {14},
year = {2006}
}
@article{Sauve2006,
abstract = {Sirtuins are a family of NAD+-dependent protein deacetylases widely distributed in all phyla of life. Accumulating evidence indicates that sirtuins are important regulators of organism life span. In yeast, these unique enzymes regulate gene silencing by histone deacetylation and via formation of the novel compound 2'-O-acetyl-ADP-ribose. In multicellular organisms, sirtuins deacetylate histones and transcription factors that regulate stress, metabolism, and survival pathways. The chemical mechanism of sirtuins provides novel opportunities for signaling and metabolic regulation of protein deacetylation. The biological, chemical, and structural characteristics of these unusual enzymes are discussed in this review.},
author = {Sauve, Anthony a and Wolberger, Cynthia and Schramm, Vern L and Boeke, Jef D},
doi = {10.1146/annurev.biochem.74.082803.133500},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/The biochemistry of sirtuins.pdf:pdf},
issn = {0066-4154},
journal = {Annual review of biochemistry},
keywords = {ADP Ribose Transferases,ADP Ribose Transferases: metabolism,Aging,Aging: physiology,Amino Acid Sequence,Animals,Caloric Restriction,Humans,Molecular Sequence Data,Molecular Structure,Multigene Family,NAD,NAD: chemistry,NAD: metabolism,O-Acetyl-ADP-Ribose,O-Acetyl-ADP-Ribose: metabolism,Protein Conformation,Protein Isoforms,Protein Isoforms: chemistry,Protein Isoforms: genetics,Protein Isoforms: metabolism,Sequence Alignment,Sirtuins,Sirtuins: chemistry,Sirtuins: genetics,Sirtuins: metabolism},
month = jan,
pages = {435--65},
pmid = {16756498},
title = {{The biochemistry of sirtuins.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16756498},
volume = {75},
year = {2006}
}
@article{Smith2006,
author = {Smith, Brian C and Denu, John M},
doi = {10.1016/j.str.2006.07.004},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1-s2.0-S0969212606003066-main.pdf:pdf},
issn = {0969-2126},
journal = {Structure (London, England : 1993)},
keywords = {Catalysis,Lysine,Lysine: metabolism,Models, Molecular,Sirtuins,Sirtuins: chemistry,Sirtuins: metabolism},
month = aug,
number = {8},
pages = {1207--8},
pmid = {16905094},
title = {{Sirtuins caught in the act.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/16905094},
volume = {14},
year = {2006}
}
@article{Warren2006,
author = {Warren, GL and Andrews, CW},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm050362n.pdf:pdf},
journal = {Journal of Medicinal Chemistry},
pages = {5912--5931},
title = {{A critical assessment of docking programs and scoring functions}},
url = {http://pubs.acs.org/doi/abs/10.1021/jm050362n},
volume = {49},
year = {2006}
}
@article{Lu2007,
abstract = {We have studied room-temperature structural and dynamic properties of the p53 DNA-binding domain in both DNA-bound and DNA-free states. A cumulative 55 ns of explicit solvent molecular dynamics simulations with the particle mesh Ewald treatment of electrostatics was performed. It was found that the mean structures in the production portions of the trajectories agree well with the crystal structure: backbone root-mean-square deviations are in the range of 1.6 and 2.0 A. In both simulations, noticeable backbone deviations from the crystal structure are observed only in loop L6, due to the lack of crystal packing in the simulations. More deviations are observed in the DNA-free simulation, apparently due to the absence of DNA. Computed backbone B-factor is also in qualitative agreement with the crystal structure. Interestingly, little backbone structural change is observed between the mean simulated DNA-bound and DNA-free structures. A notable difference is observed only at the DNA-binding interface. The correlation between native contacts and inactivation mechanisms of tumor mutations is also discussed. In the H2 region, tumor mutations at sites D281, R282, E285, and E286 may weaken five key interactions that stabilize H2, indicating that their inactivation mechanisms may be related to the loss of local structure around H2, which in turn may reduce the overall stability to a measurable amount. In the L2 region, tumor mutations at sites Y163, K164, E171, V173, L194, R249, I251, and E271 are likely to be responsible for the loss of stability in the protein. In addition to apparent DNA contacts that are related to DNA binding, interactions R175/S183, S183/R196, and E198/N235 are highly occupied only in the DNA-bound form, indicating that they are more likely to be responsible for DNA binding.},
author = {Lu, Qiang and Tan, Yu-hong and Luo, Ray},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jp0742261.pdf:pdf},
institution = {Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92697-3900, USA.},
journal = {Journal of Physical Chemistry B},
number = {39},
pages = {11538--11545},
title = {{Molecular Dynamics Simulations of p53 DNA-Binding Domain}},
url = {http://dx.doi.org/10.1021/jp0742261},
volume = {111},
year = {2007}
}
@article{Numata2007,
author = {Numata, Jorge and Wan, M and Knapp, EW},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/IBSB07019.pdf:pdf},
journal = {Genome Inform},
keywords = {anharmonicity,conformational entropy,harmonic approximation,k-nearest neighbor entropy,principal component analysis,quasi-,vibrational entropy},
number = {1},
pages = {192--205},
title = {{Conformational entropy of biomolecules: beyond the quasi-harmonic approximation}},
url = {http://jsbi2013.sakura.ne.jp/pdfs/journal1/IBSB07/IBSB07019.pdf},
year = {2007}
}
@article{Outeiro2007,
abstract = {The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.},
author = {Outeiro, Tiago Fleming and Kontopoulos, Eirene and Altmann, Stephen M and Kufareva, Irina and Strathearn, Katherine E and Amore, Allison M and Volk, Catherine B and Maxwell, Michele M and Rochet, Jean-Christophe and McLean, Pamela J and Young, Anne B and Abagyan, Ruben and Feany, Mel B and Hyman, Bradley T and Kazantsev, Aleksey G},
doi = {10.1126/science.1143780},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/Outeiro-SOM.pdf:pdf},
issn = {1095-9203},
journal = {Science (New York, N.Y.)},
keywords = {Acetylation,Animals,Animals, Genetically Modified,Cell Death,Cell Death: drug effects,Cell Line, Tumor,Cells, Cultured,Disease Models, Animal,Dopamine,Dopamine: physiology,Dose-Response Relationship, Drug,Drosophila melanogaster,Furans,Furans: pharmacology,Humans,Models, Molecular,Neurons,Neurons: cytology,Neurons: drug effects,Parkinson Disease,Parkinson Disease: drug therapy,Parkinson Disease: metabolism,Parkinson Disease: pathology,Parkinson Disease: physiopathology,Protein Conformation,Quinolines,Quinolines: pharmacology,RNA, Small Interfering,RNA, Small Interfering: genetics,Rats,Sirtuin 1,Sirtuin 2,Sirtuins,Sirtuins: antagonists \& inhibitors,Sirtuins: chemistry,Sirtuins: genetics,Sirtuins: metabolism,Transfection,Tubulin,Tubulin: metabolism,alpha-Synuclein,alpha-Synuclein: genetics,alpha-Synuclein: metabolism},
month = jul,
number = {5837},
pages = {516--9},
pmid = {17588900},
title = {{Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17588900},
volume = {317},
year = {2007}
}
@article{Outeiro2007a,
abstract = {The sirtuins are members of the histone deacetylase family of proteins that participate in a variety of cellular functions and play a role in aging. We identified a potent inhibitor of sirtuin 2 (SIRT2) and found that inhibition of SIRT2 rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of Parkinson's disease. Genetic inhibition of SIRT2 via small interfering RNA similarly rescued alpha-synuclein toxicity. Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging.},
author = {Outeiro, Tiago Fleming and Kontopoulos, Eirene and Altmann, Stephen M and Kufareva, Irina and Strathearn, Katherine E and Amore, Allison M and Volk, Catherine B and Maxwell, Michele M and Rochet, Jean-Christophe and McLean, Pamela J and Young, Anne B and Abagyan, Ruben and Feany, Mel B and Hyman, Bradley T and Kazantsev, Aleksey G},
doi = {10.1126/science.1143780},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/Science-2007-Outeiro-516-9.pdf:pdf},
issn = {1095-9203},
journal = {Science (New York, N.Y.)},
keywords = {Acetylation,Animals,Animals, Genetically Modified,Cell Death,Cell Death: drug effects,Cell Line, Tumor,Cells, Cultured,Disease Models, Animal,Dopamine,Dopamine: physiology,Dose-Response Relationship, Drug,Drosophila melanogaster,Furans,Furans: pharmacology,Humans,Models, Molecular,Neurons,Neurons: cytology,Neurons: drug effects,Parkinson Disease,Parkinson Disease: drug therapy,Parkinson Disease: metabolism,Parkinson Disease: pathology,Parkinson Disease: physiopathology,Protein Conformation,Quinolines,Quinolines: pharmacology,RNA, Small Interfering,RNA, Small Interfering: genetics,Rats,Sirtuin 1,Sirtuin 2,Sirtuins,Sirtuins: antagonists \& inhibitors,Sirtuins: chemistry,Sirtuins: genetics,Sirtuins: metabolism,Transfection,Tubulin,Tubulin: metabolism,alpha-Synuclein,alpha-Synuclein: genetics,alpha-Synuclein: metabolism},
month = jul,
number = {5837},
pages = {516--9},
pmid = {17588900},
title = {{Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/17588900},
volume = {317},
year = {2007}
}
@article{Su2007,
author = {Su, Yang and Gallicchio, Emilio and Das, Kalyan and Arnold, Eddy and Levy, Ronald M.},
doi = {10.1021/ct600258e},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ct600258e.pdf:pdf},
issn = {1549-9618},
journal = {Journal of Chemical Theory and Computation},
month = jan,
number = {1},
pages = {256--277},
title = {{Linear Interaction Energy (LIE) Models for Ligand Binding in Implicit Solvent:  Theory and Application to the Binding of NNRTIs to HIV-1 Reverse Transcriptase}},
url = {http://pubs.acs.org/doi/abs/10.1021/ct600258e},
volume = {3},
year = {2007}
}
@article{Guimaraes2008,
abstract = {The critical issues in docking include the prediction of the correct binding pose and the accurate estimation of the corresponding binding affinity. Different docking methodologies have all been successful in reproducing the crystallographic binding modes but struggle when predicting the corresponding binding affinities. The aim of this work is to evaluate the performance of the MM-GB/SA rescoring of docking poses in structure-based lead optimization. To accomplish that, a diverse set of pharmaceutically relevant targets, including CDK2, FactorXa, Thrombin, and HIV-RT were selected. The correlation between the MM-GB/SA results and experimental data in all cases is remarkable. It even qualifies this approach as a more attractive alternative for rank-ordering than the Free Energy Perturbation and Thermodynamic Integration methodologies because, while as accurate, it can handle more structurally dissimilar ligands and provides results at a fraction of the computational cost. On the technical side, the benefit of performing a conformational analysis and having an ensemble of conformers to represent each ligand in the unbound state during the MM-GB/SA rescoring procedure was investigated. In addition, the estimation of conformational entropy penalties for the ligands upon binding, computed from the Boltzmann distribution in water, was evaluated and compared to a commonly used approach employed by many docking scoring functions.},
author = {Guimar\~{a}es, Cristiano R W and Cardozo, Mario},
doi = {10.1021/ci800004w},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ci800004w.pdf:pdf},
issn = {1549-9596},
journal = {Journal of chemical information and modeling},
keywords = {Cyclin-Dependent Kinase 2,Cyclin-Dependent Kinase 2: metabolism,Drug Evaluation, Preclinical,Drug Evaluation, Preclinical: methods,Entropy,Enzyme Inhibitors,Enzyme Inhibitors: chemistry,Enzyme Inhibitors: metabolism,Factor Xa,Factor Xa: metabolism,HIV Reverse Transcriptase,HIV Reverse Transcriptase: metabolism,Ligands,Models, Molecular,Protein Binding,Protein Conformation,Solvents,Solvents: chemistry,Thrombin,Thrombin: metabolism,Water,Water: chemistry},
month = may,
number = {5},
pages = {958--70},
pmid = {18422307},
title = {{MM-GB/SA rescoring of docking poses in structure-based lead optimization.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18422307},
volume = {48},
year = {2008}
}
@article{Milne2008,
abstract = {Sirtuins have emerged as therapeutic targets to treat age-related diseases. There are seven human Sirtuins (SIRT1-7) that display diversity in cellular localization and function. Growing evidence suggests that small-molecule activators of SIRT1 may counteract age-related afflictions such as type 2 diabetes. Alternatively, inhibitors of SIRT2 may be useful in the treatment of neurodegenerative diseases such as Parkinson's disease. Recent discoveries of small-molecule and protein modulators of Sirtuin deacetylation activity have provided enormous insight into the biological and molecular functions of Sirtuins and have validated their potential as therapeutics.},
author = {Milne, Jill C and Denu, John M},
doi = {10.1016/j.cbpa.2008.01.019},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1-s2.0-S1367593108000112-main.pdf:pdf},
issn = {1367-5931},
journal = {Current Opinion in Chemical Biology},
keywords = {Aging,Aging: pathology,Drug Design,Enzyme Activation,Enzyme Activation: drug effects,Enzyme Inhibitors,Enzyme Inhibitors: metabolism,Enzyme Inhibitors: pharmacology,Enzyme Inhibitors: therapeutic use,Geriatrics,Humans,Sirtuins,Sirtuins: agonists,Sirtuins: antagonists \& inhibitors,Sirtuins: metabolism},
month = feb,
number = {1},
pages = {11--17},
pmid = {18282481},
shorttitle = {The Sirtuin family},
title = {{The Sirtuin family: therapeutic targets to treat diseases of aging}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18282481},
volume = {12},
year = {2008}
}
@article{Neugebauer2008,
abstract = {NAD (+)-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysines in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of those enzymes and may be future drugs for the treatment of cancer. Splitomicin was among the first two inhibitors that were discovered for yeast sirtuins but showed rather weak inhibition on human enzymes. We present detailed structure-activity relationships on splitomicin derivatives and their inhibition of recombinant Sirt2. To rationalize our experimental results, ligand docking followed by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations were carried out. These analyses suggested a molecular basis for the interaction of the beta-phenylsplitomicins with human Sirt2. Protein-based virtual screening resulted in the identification of a novel Sirt2 inhibitor chemotype. Selected inhibitors showed antiproliferative properties and tubulin hyperacetylation in MCF7 breast cancer cells and are promising candidates for further optimization as potential anticancer drugs.},
author = {Neugebauer, Robert C and Uchiechowska, Urszula and Meier, Rene and Hruby, Henning and Valkov, Vassil and Verdin, Eric and Sippl, Wolfgang and Jung, Manfred},
doi = {10.1021/jm700972e},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm700972e.pdf:pdf},
issn = {0022-2623},
journal = {Journal of medicinal chemistry},
keywords = {Acetylation,Antineoplastic Agents,Antineoplastic Agents: chemical synthesis,Antineoplastic Agents: chemistry,Antineoplastic Agents: pharmacology,Catalytic Domain,Cell Line, Tumor,Databases, Factual,Drug Screening Assays, Antitumor,Humans,Hydrogen Bonding,Models, Molecular,Naphthalenes,Naphthalenes: chemical synthesis,Naphthalenes: chemistry,Naphthalenes: pharmacology,Protein Binding,Pyrones,Pyrones: chemical synthesis,Pyrones: chemistry,Pyrones: pharmacology,Recombinant Proteins,Recombinant Proteins: antagonists \& inhibitors,Recombinant Proteins: chemistry,Sirtuin 2,Sirtuins,Sirtuins: antagonists \& inhibitors,Sirtuins: chemistry,Stereoisomerism,Structure-Activity Relationship,Thermodynamics,Tubulin,Tubulin: chemistry},
month = mar,
number = {5},
pages = {1203--13},
pmid = {18269226},
title = {{Structure-activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18269226},
volume = {51},
year = {2008}
}
@article{Taylor2008,
abstract = {Sirtuins comprise a unique class of nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases that target multiple protein substrates to execute diverse biological functions. These enzymes are key regulators of clinically important cellular and organismal processes, including metabolism, cell division and aging. The desire to understand the important determinants of human health and lifespan has resulted in a firestorm of work on the seven mammalian sirtuins in less than a decade. The implication of sirtuins in medically important areas such as diabetes, cancer, cardiovascular dysfunction and neurodegenerative disease has further catapulted them to a prominent status as potential targets for nutritional and therapeutic development. Here, we present a review of published results on sirtuin biology and its relevance to human disease.},
author = {Taylor, D M and Maxwell, M M and Luthi-Carter, R and Kazantsev, a G},
doi = {10.1007/s00018-008-8357-y},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/10.1007-s00018-008-8357-y.pdf:pdf},
issn = {1420-9071},
journal = {Cellular and molecular life sciences : CMLS},
keywords = {Amino Acid Sequence,Animals,Disease,Histone Deacetylases,Histone Deacetylases: chemistry,Histone Deacetylases: metabolism,Histone Deacetylases: therapeutic use,Humans,Metabolic Networks and Pathways,Molecular Sequence Data,Sequence Homology, Amino Acid,Sirtuins,Sirtuins: chemistry,Sirtuins: metabolism,Sirtuins: therapeutic use,Substrate Specificity},
month = dec,
number = {24},
pages = {4000--18},
pmid = {18820996},
title = {{Biological and potential therapeutic roles of sirtuin deacetylases.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18820996},
volume = {65},
year = {2008}
}
@article{Uciechowska2008,
abstract = {NAD+-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysine residues in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of these enzymes and may be future drugs for the treatment of cancer or neurodegenerative diseases. Herein we present the results from a protein-based virtual screen of a commercial database with subsequent biological testing of the most promising compounds. The combination of docking and in vitro experimental testing resulted in the identification of novel sirtuin inhibitors with thiobarbiturate structure. To rationalize the experimental results, free-energy calculations were carried out by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations. A significant correlation between calculated binding free energies and measured Sirt2 inhibitory activities was observed. The analyses suggested a molecular basis for the interaction of the identified thiobarbiturate derivatives with human Sirt2. Based on the docking and MM-PBSA calculations we synthesized and tested five further thiobarbiturates. The MM-PBSA method correctly predicted the activity of the novel thiobarbiturates. The identified compounds will be used to further explore the therapeutic potential of sirtuin inhibitors.},
author = {Uciechowska, Urszula and Schemies, J\"{o}rg and Neugebauer, Robert C and Huda, Elisabeth-Maria and Schmitt, Martin L and Meier, Rene and Verdin, Eric and Jung, Manfred and Sippl, Wolfgang},
doi = {10.1002/cmdc.200800104},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1965\_ftp.pdf:pdf},
issn = {1860-7187},
journal = {ChemMedChem},
keywords = {Algorithms,Binding Sites,Computer Simulation,Databases, Factual,Drug Design,Enzyme Inhibitors,Enzyme Inhibitors: chemical synthesis,Enzyme Inhibitors: chemistry,Enzyme Inhibitors: pharmacology,Humans,Models, Molecular,Sirtuins,Sirtuins: antagonists \& inhibitors,Sirtuins: pharmacology,Spectrometry, Fluorescence,Structure-Activity Relationship,Thermodynamics,Thiobarbiturates,Thiobarbiturates: chemical synthesis,Thiobarbiturates: chemistry,Thiobarbiturates: pharmacology},
month = dec,
number = {12},
pages = {1965--76},
pmid = {18985648},
title = {{Thiobarbiturates as sirtuin inhibitors: virtual screening, free-energy calculations, and biological testing.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/18985648},
volume = {3},
year = {2008}
}
@article{Clark2009,
abstract = {Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.},
author = {Clark, Matthew a and Acharya, Raksha a and Arico-Muendel, Christopher C and Belyanskaya, Svetlana L and Benjamin, Dennis R and Carlson, Neil R and Centrella, Paolo a and Chiu, Cynthia H and Creaser, Steffen P and Cuozzo, John W and Davie, Christopher P and Ding, Yun and Franklin, G Joseph and Franzen, Kurt D and Gefter, Malcolm L and Hale, Steven P and Hansen, Nils J V and Israel, David I and Jiang, Jinwei and Kavarana, Malcolm J and Kelley, Michael S and Kollmann, Christopher S and Li, Fan and Lind, Kenneth and Mataruse, Sibongile and Medeiros, Patricia F and Messer, Jeffrey a and Myers, Paul and O'Keefe, Heather and Oliff, Matthew C and Rise, Cecil E and Satz, Alexander L and Skinner, Steven R and Svendsen, Jennifer L and Tang, Lujia and van Vloten, Kurt and Wagner, Richard W and Yao, Gang and Zhao, Baoguang and Morgan, Barry a},
doi = {10.1038/nchembio.211},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/nchembio.211.pdf:pdf},
issn = {1552-4469},
journal = {Nature chemical biology},
keywords = {Animals,Combinatorial Chemistry Techniques,DNA,DNA: chemistry,DNA: genetics,Drug Design,Models, Molecular,Protein Kinase Inhibitors,Protein Kinase Inhibitors: chemical synthesis,Protein Kinase Inhibitors: chemistry,Protein Kinase Inhibitors: pharmacology,Protein-Serine-Threonine Kinases,Protein-Serine-Threonine Kinases: antagonists \& inhibitors,Small Molecule Libraries,Small Molecule Libraries: chemical synthesis,Small Molecule Libraries: chemistry,Small Molecule Libraries: pharmacology,p38 Mitogen-Activated Protein Kinases,p38 Mitogen-Activated Protein Kinases: antagonists \& inhibitors},
month = sep,
number = {9},
pages = {647--54},
pmid = {19648931},
title = {{Design, synthesis and selection of DNA-encoded small-molecule libraries.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19648931},
volume = {5},
year = {2009}
}
@article{Cross2009,
author = {Cross, JB and Thompson, DC},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ci900056c.pdf:pdf},
journal = {Journal of chemical information and modeling},
pages = {1455--1474},
title = {{Comparison of several molecular docking programs: pose prediction and virtual screening accuracy}},
url = {http://pubs.acs.org/doi/abs/10.1021/ci900056c},
volume = {49},
year = {2009}
}
@article{Jin2009,
abstract = {SIRT3 is a major mitochondrial NAD(+)-dependent protein deacetylase playing important roles in regulating mitochondrial metabolism and energy production and has been linked to the beneficial effects of exercise and caloric restriction. SIRT3 is emerging as a potential therapeutic target to treat metabolic and neurological diseases. We report the first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide, and a structure with the dethioacetylated peptide bound. These structures provide insights into the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD(+). In addition, the binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, before NAD(+). These structures and biophysical studies provide key insight into the structural and functional relationship of the SIRT3 deacetylation activity.},
author = {Jin, Lei and Wei, Wentao and Jiang, Yaobin and Peng, Hao and Cai, Jianhua and Mao, Chen and Dai, Han and Choy, Wendy and Bemis, Jean E and Jirousek, Michael R and Milne, Jill C and Westphal, Christoph H and Perni, Robert B},
doi = {10.1074/jbc.M109.014928},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/J. Biol. Chem.-2009-Jin-24394-405.pdf:pdf},
issn = {0021-9258},
journal = {The Journal of biological chemistry},
keywords = {Acetate-CoA Ligase,Acetate-CoA Ligase: chemistry,Acetate-CoA Ligase: metabolism,Acetylation,Humans,Mitochondria,Mitochondria: enzymology,Mitochondrial Proteins,Mitochondrial Proteins: chemistry,Mitochondrial Proteins: metabolism,NAD,NAD: chemistry,Peptides,Peptides: chemistry,Peptides: metabolism,Protein Binding,Protein Binding: physiology,Protein Structure, Quaternary,Sirtuin 3,Sirtuins,Sirtuins: chemistry,Sirtuins: metabolism,Structure-Activity Relationship},
month = sep,
number = {36},
pages = {24394--405},
pmid = {19535340},
title = {{Crystal structures of human SIRT3 displaying substrate-induced conformational changes.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2782032\&tool=pmcentrez\&rendertype=abstract},
volume = {284},
year = {2009}
}
@article{Okimoto2009,
abstract = {Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, this method is not completely reliable and therefore unsatisfactory. In this study, we used massive molecular dynamics simulations of protein-ligand conformations obtained by molecular docking in order to improve the enrichment performance of molecular docking. Our screening approach employed the molecular mechanics/Poisson-Boltzmann and surface area method to estimate the binding free energies. For the top-ranking 1,000 compounds obtained by docking to a target protein, approximately 6,000 molecular dynamics simulations were performed using multiple docking poses in about a week. As a result, the enrichment performance of the top 100 compounds by our approach was improved by 1.6-4.0 times that of the enrichment performance of molecular dockings. This result indicates that the application of molecular dynamics simulations to virtual screening for lead discovery is both effective and practical. However, further optimization of the computational protocols is required for screening various target proteins.},
author = {Okimoto, Noriaki and Futatsugi, Noriyuki and Fuji, Hideyoshi and Suenaga, Atsushi and Morimoto, Gentaro and Yanai, Ryoko and Ohno, Yousuke and Narumi, Tetsu and Taiji, Makoto},
doi = {10.1371/journal.pcbi.1000528},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/journal.pcbi.1000528.pdf:pdf},
issn = {1553-7358},
journal = {PLoS computational biology},
keywords = {Acetylcholinesterase,Acetylcholinesterase: chemistry,Acetylcholinesterase: metabolism,Area Under Curve,Binding Sites,Computational Biology,Computational Biology: methods,Computer Simulation,Crystallography, X-Ray,Cyclin-Dependent Kinase 2,Cyclin-Dependent Kinase 2: chemistry,Cyclin-Dependent Kinase 2: metabolism,Drug Discovery,Drug Discovery: methods,HIV Protease,HIV Protease: chemistry,HIV Protease: metabolism,Ligands,Models, Chemical,Models, Molecular,Pharmacokinetics,ROC Curve,Thermodynamics,Trypsin,Trypsin: chemistry,Trypsin: metabolism},
month = oct,
number = {10},
pages = {e1000528},
pmid = {19816553},
title = {{High-performance drug discovery: computational screening by combining docking and molecular dynamics simulations.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2746282\&tool=pmcentrez\&rendertype=abstract},
volume = {5},
year = {2009}
}
@article{Zhang2009,
abstract = {As a member of the class III histone deacetylases, Sirtuin-2 (SIRT2) is critical in cell cycle regulation which makes it a potential target for cancer therapeutics. In this study, we identified a novel SIRT2 inhibitor, AC-93253, with IC(50) of 6 microM in vitro. The compound is selective, inhibiting SIRT2 7.5- and 4-fold more potently than the closely related SIRT1 and SIRT3, respectively. AC-93253 significantly enhanced acetylation of tubulin, p53, and histone H4, confirming SIRT2 and SIRT1 as its cellular targets. AC-93253 as a single agent exhibited submicromolar selective cytotoxicity towards all four tumor cell lines tested with a therapeutic window up to 200-fold, comparing to any of the three normal cell types tested. Results from high content analysis suggested that AC-93253 significantly triggered apoptosis. Taken together, SIRT2 selective inhibitor AC-93253 may serve as a novel chemical scaffold for structure-activity relationship study and future lead development.},
author = {Zhang, Yingjia and Au, Qingyan and Zhang, Menghua and Barber, Jack R and Ng, Shi Chung and Zhang, Bin},
doi = {10.1016/j.bbrc.2009.06.113},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1-s2.0-S0006291X09012698-main.pdf:pdf},
issn = {1090-2104},
journal = {Biochemical and biophysical research communications},
keywords = {Antineoplastic Agents,Antineoplastic Agents: chemistry,Antineoplastic Agents: isolation \& purification,Antineoplastic Agents: pharmacology,Benzothiazoles,Benzothiazoles: chemistry,Benzothiazoles: isolation \& purification,Benzothiazoles: pharmacology,Cell Line, Tumor,Enzyme Inhibitors,Enzyme Inhibitors: chemistry,Enzyme Inhibitors: isolation \& purification,Enzyme Inhibitors: pharmacology,Humans,Inhibitory Concentration 50,Sirtuin 2,Sirtuins,Sirtuins: antagonists \& inhibitors},
month = sep,
number = {4},
pages = {729--33},
pmid = {19559674},
publisher = {Elsevier Inc.},
title = {{Identification of a small molecule SIRT2 inhibitor with selective tumor cytotoxicity.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19559674},
volume = {386},
year = {2009}
}
@article{Cen2010,
abstract = {Accumulating evidence has indicated the importance of sirtuins (class III histone deacetylases) in various biological processes. Their potential roles in metabolic and neurodegenerative diseases have encouraged scientists to seek potent and selective sirtuin inhibitors to investigate their biological functions with a view to eventual new therapeutic treatments. This article surveys current knowledge of sirtuin inhibitors including those discovered via high-throughput screening (HST) or via mechanism-based drug design from synthetic or natural sources. Their inhibitory affinity, selectivities, and possible inhibition mechanisms are discussed.},
author = {Cen, Yana},
doi = {10.1016/j.bbapap.2009.11.010},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1-s2.0-S1570963909003434-main.pdf:pdf},
issn = {0006-3002},
journal = {Biochimica Et Biophysica Acta},
keywords = {Animals,Drug Design,Drug Evaluation, Preclinical,Enzyme Inhibitors,Enzyme Inhibitors: chemistry,Enzyme Inhibitors: metabolism,Enzyme Inhibitors: pharmacology,Humans,Models, Molecular,NAD,NAD: metabolism,Sirtuins,Sirtuins: antagonists \& inhibitors,Sirtuins: chemistry,Sirtuins: metabolism,Structure-Activity Relationship},
month = aug,
number = {8},
pages = {1635--1644},
pmid = {19931429},
shorttitle = {Sirtuins inhibitors},
title = {{Sirtuins inhibitors: the approach to affinity and selectivity}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/19931429},
volume = {1804},
year = {2010}
}
@article{Korb2010,
author = {Korb, Oliver and Bowden, S and Olsson, T and Frenkel, D and Liebeschuetz, J and Cole, J},
doi = {10.1186/1758-2946-2-S1-P25},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/EuroCUP4\_Korb.pdf:pdf},
issn = {1758-2946},
journal = {Journal of Cheminformatics},
number = {Suppl 1},
pages = {P25},
title = {{Ensemble docking revisited}},
url = {http://www.jcheminf.com/content/2/S1/P25},
volume = {2},
year = {2010}
}
@article{Lawson2010,
abstract = {Histone deacetylases (HDACs) are enzymes that cleave acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Unlike the other three of the four classes of HDACs that have been identified in humans, which are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD(+)) for their catalytic activity. The seven members of the class III HDACs are also named sirtuins for their homology to Sir2p, a yeast histone deacetylase. Sirtuin inhibitors have been critical for the linkage of sirtuin activity to many physiological and pathological processes, and sirtuin activity has been associated with the pathogenesis of cancer, HIV, and metabolic and neurological diseases. Presented here is an overview of the many sirtuin inhibitors that have provided insight into the biological role of sirtuins.},
author = {Lawson, Michael and Uciechowska, Urszula and Schemies, J\"{o}rg and Rumpf, Tobias and Jung, Manfred and Sippl, Wolfgang},
doi = {10.1016/j.bbagrm.2010.06.003},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1-s2.0-S1874939910000805-main.pdf:pdf},
issn = {0006-3002},
journal = {Biochimica et biophysica acta},
keywords = {Animals,HIV Infections,HIV Infections: drug therapy,HIV Infections: enzymology,Histone Deacetylase Inhibitors,Histone Deacetylase Inhibitors: chemistry,Histone Deacetylase Inhibitors: metabolism,Histone Deacetylase Inhibitors: therapeutic use,Humans,Metabolic Diseases,Metabolic Diseases: drug therapy,Metabolic Diseases: enzymology,NAD,NAD: chemistry,NAD: metabolism,Neoplasms,Neoplasms: drug therapy,Neoplasms: enzymology,Nervous System Diseases,Nervous System Diseases: drug therapy,Nervous System Diseases: enzymology,Sirtuins,Sirtuins: chemistry,Sirtuins: metabolism},
number = {10-12},
pages = {726--39},
pmid = {20601279},
publisher = {Elsevier B.V.},
title = {{Inhibitors to understand molecular mechanisms of NAD(+)-dependent deacetylases (sirtuins).}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/20601279},
volume = {1799},
year = {2010}
}
@article{Rastelli2010,
author = {Rastelli, Giulio and Rio, AD and Degliesposti, G and Sgobba, M},
doi = {10.1002/jcc},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/21372\_ftp.pdf:pdf},
journal = {International Journal of Computational Chemistry},
keywords = {binding free energy prediction,drug design,mm-gbsa,mm-pbsa,virtual screening},
pages = {797--810},
title = {{Fast and accurate predictions of binding free energies using MM‐PBSA and MM‐GBSA}},
url = {http://onlinelibrary.wiley.com/doi/10.1002/jcc.21372/full},
volume = {31},
year = {2010}
}
@article{Dolghih2011,
abstract = {P-glycoprotein (P-gp) is an ATP-dependent transport protein that is selectively expressed at entry points of xenobiotics where, acting as an efflux pump, it prevents their entering sensitive organs. The protein also plays a key role in the absorption and blood-brain barrier penetration of many drugs, while its overexpression in cancer cells has been linked to multidrug resistance in tumors. The recent publication of the mouse P-gp crystal structure revealed a large and hydrophobic binding cavity with no clearly defined sub-sites that supports an "induced-fit" ligand binding model. We employed flexible receptor docking to develop a new prediction algorithm for P-gp binding specificity. We tested the ability of this method to differentiate between binders and nonbinders of P-gp using consistently measured experimental data from P-gp efflux and calcein-inhibition assays. We also subjected the model to a blind test on a series of peptidic cysteine protease inhibitors, confirming the ability to predict compounds more likely to be P-gp substrates. Finally, we used the method to predict cellular metabolites that may be P-gp substrates. Overall, our results suggest that many P-gp substrates bind deeper in the cavity than the cyclic peptide in the crystal structure and that specificity in P-gp is better understood in terms of physicochemical properties of the ligands (and the binding site), rather than being defined by specific sub-sites.},
author = {Dolghih, Elena and Bryant, Clifford and Renslo, Adam R and Jacobson, Matthew P},
doi = {10.1371/journal.pcbi.1002083},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/journal.pcbi.1002083.pdf:pdf},
issn = {1553-7358},
journal = {PLoS computational biology},
keywords = {Algorithms,Animals,Binding Sites,Cell Line,Cysteine Proteinase Inhibitors,Cysteine Proteinase Inhibitors: chemistry,Cysteine Proteinase Inhibitors: metabolism,Dogs,Drug Discovery,Humans,Mice,Molecular Dynamics Simulation,P-Glycoprotein,P-Glycoprotein: chemistry,P-Glycoprotein: metabolism,Pharmacokinetics,Pliability,Protein Binding,ROC Curve},
month = jun,
number = {6},
pages = {e1002083},
pmid = {21731480},
title = {{Predicting binding to p-glycoprotein by flexible receptor docking.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3121697\&tool=pmcentrez\&rendertype=abstract},
volume = {7},
year = {2011}
}
@article{Schlicker2011,
abstract = {Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Mammalia possess seven Sirtuin isoforms, Sirt1-7, which differ in their subcellular localization and in the substrate proteins they deacetylate. The physiological roles of Sirtuins and their potential use as therapeutic targets for metabolic and aging-related diseases have spurred interest in the development of small-molecule Sirtuin modulators. Here, we describe an approach exploiting the structures available for four human Sirtuins for the development of isoform-specific inhibitors. Virtual docking of a compound library into the peptide binding pockets of crystal structures of Sirt2, 3, 5 and 6 yielded compounds potentially discriminating between these isoforms. Further characterization in activity assays revealed several inhibitory compounds with little isoform specificity, but also two compounds with micromolar potency and high specificity for Sirt2. Structure comparison and the predicted, shared binding mode of the Sirt2-specific compounds indicate a pocket extending from the peptide-binding groove as target side enabling isoform specificity. Our family-wide structure-based approach thus identified potent, Sirt2-specific inhibitors as well as lead structures and a target site for the development of compounds specific for other Sirtuin isoform, constituting an important step toward the identification of a complete panel of isoform-specific Sirtuin inhibitors.},
author = {Schlicker, Christine and Boanca, Gina and Lakshminarasimhan, Mahadevan and Steegborn, Clemens},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/aging-03-852.pdf:pdf},
issn = {1945-4589},
journal = {Aging},
keywords = {Cell Line,Computer Simulation,Drug Design,Enzyme Inhibitors,Enzyme Inhibitors: chemistry,Enzyme Inhibitors: metabolism,Humans,Isoenzymes,Isoenzymes: antagonists \& inhibitors,Isoenzymes: chemistry,Isoenzymes: genetics,Ligands,Models, Molecular,Molecular Structure,Protein Binding,Protein Conformation,Sirtuins,Sirtuins: antagonists \& inhibitors,Sirtuins: chemistry,Sirtuins: genetics,Structure-Activity Relationship},
month = sep,
number = {9},
pages = {852--72},
pmid = {21937767},
title = {{Structure-based development of novel sirtuin inhibitors.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3227451\&tool=pmcentrez\&rendertype=abstract},
volume = {3},
year = {2011}
}
@article{Gertz2012,
abstract = {Sirtuins are protein deacetylases regulating metabolism, stress responses, and aging processes, and they were suggested to mediate the lifespan extending effect of a low calorie diet. Sirtuin activation by the polyphenol resveratrol can mimic such lifespan extending effects and alleviate metabolic diseases. The mechanism of Sirtuin stimulation is unknown, hindering the development of improved activators. Here we show that resveratrol inhibits human Sirt3 and stimulates Sirt5, in addition to Sirt1, against fluorophore-labeled peptide substrates but also against peptides and proteins lacking the non-physiological fluorophore modification. We further present crystal structures of Sirt3 and Sirt5 in complex with fluorogenic substrate peptide and modulator. The compound acts as a top cover, closing the Sirtuin's polypeptide binding pocket and influencing details of peptide binding by directly interacting with this substrate. Our results provide a mechanism for the direct activation of Sirtuins by small molecules and suggest that activators have to be tailored to a specific Sirtuin/substrate pair.},
author = {Gertz, Melanie and Nguyen, GTT and Fischer, Frank},
doi = {10.1371/journal.pone.0049761},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/journal.pone.0049761.pdf:pdf},
issn = {1932-6203},
journal = {PloS one},
keywords = {Acetylation,Acetylation: drug effects,Caloric Restriction,Crystallography,Humans,Peptides,Peptides: chemistry,Peptides: metabolism,Protein Binding,Protein Conformation,Sirtuin 1,Sirtuin 1: chemistry,Sirtuin 1: metabolism,Sirtuin 3,Sirtuin 3: chemistry,Sirtuin 3: metabolism,Sirtuins,Sirtuins: chemistry,Sirtuins: metabolism,Stilbenes,Stilbenes: pharmacology,Substrate Specificity,X-Ray},
month = jan,
number = {11},
pages = {e49761},
pmid = {23185430},
title = {{A molecular mechanism for direct sirtuin activation by resveratrol}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3504108\&tool=pmcentrez\&rendertype=abstract http://dx.plos.org/10.1371/journal.pone.0049761},
volume = {7},
year = {2012}
}
@article{Kohlmann2012,
author = {Kohlmann, Anna and Zhu, Xiaotian and Dalgarno, David},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ml200222u.pdf:pdf},
journal = {ACS Medicinal Chemistry Letter},
keywords = {cycle at pharmaceutical companies,free energy of binding,into the lead optimization,mm-gb,omputational prediction of compound,potency has for,sa,some time been integrated,src tyrosine kinase,the promise of robust,watermap},
pages = {94--99},
title = {{Application of MM-GB/SA and WaterMap to SRC kinase inhibitor potency prediction}},
url = {http://pubs.acs.org/doi/abs/10.1021/ml200222u},
volume = {3},
year = {2012}
}
@article{Korb2012,
abstract = {A major problem in structure-based virtual screening applications is the appropriate selection of a single or even multiple protein structures to be used in the virtual screening process. A priori it is unknown which protein structure(s) will perform best in a virtual screening experiment. We investigated the performance of ensemble docking, as a function of ensemble size, for eight targets of pharmaceutical interest. Starting from single protein structure docking results, for each ensemble size up to 500,000 combinations of protein structures were generated, and, for each ensemble, pose prediction and virtual screening results were derived. Comparison of single to multiple protein structure results suggests improvements when looking at the performance of the worst and the average over all single protein structures to the performance of the worst and average over all protein ensembles of size two or greater, respectively. We identified several key factors affecting ensemble docking performance, including the sampling accuracy of the docking algorithm, the choice of the scoring function, and the similarity of database ligands to the cocrystallized ligands of ligand-bound protein structures in an ensemble. Due to these factors, the prospective selection of optimum ensembles is a challenging task, shown by a reassessment of published ensemble selection protocols.},
author = {Korb, Oliver and Olsson, Tjelvar S G and Bowden, Simon J and Hall, Richard J and Verdonk, Marcel L and Liebeschuetz, John W and Cole, Jason C},
doi = {10.1021/ci2005934},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/Potential and Limitations of Ensemble Docking.pdf:pdf},
issn = {1549-960X},
journal = {Journal of chemical information and modeling},
keywords = {Algorithms,Binding Sites,Drug Delivery Systems,Drug Discovery,Ligands,Proteins,Proteins: chemistry,Small Molecule Libraries},
month = may,
number = {5},
pages = {1262--74},
pmid = {22482774},
title = {{Potential and limitations of ensemble docking.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22482774},
volume = {52},
year = {2012}
}
@article{Linder2012,
author = {Linder, Mats and Ranganathan, Anirudh and Brinck, Tore},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ct300783e.pdf:pdf},
journal = {Journal of Chemical Theory and Computation},
number = {1},
pages = {1230--1239},
title = {{“Adapted Linear Interaction Energy”: A Structure-Based LIE Parametrization for Fast Prediction of Protein–Ligand Affinities}},
url = {http://pubs.acs.org/doi/full/10.1021/ct300783e},
volume = {9},
year = {2012}
}
@article{Papamokos2012,
abstract = {The current understanding of epigenetic signaling assigns a central role to post-translational modifications that occur in the histone tails. In this context, it has been proposed that methylation of K9 and phosphorylation of S10 in the tail of histone H3 represent a binary switch that controls its reversible association to heterochromatin protein 1 (HP1). To test this hypothesis, we performed a comprehensive molecular dynamics study in which we analyzed a crystallographically defined complex that involves the HP1 chromodomain and an H3 tail peptide. Microsecond-long simulations show that the binding of the trimethylated K9 H3 peptide in the aromatic cage of HP1 is only slightly affected by S10 phosphorylation, because the modified K9 and S10 do not interact directly with one another. Instead, the phosphate group of S10 seems to form a persistent intramolecular salt bridge with R8, an interaction that can provoke a major structural change and alter the hydrogen-bonding regime in the H3-HP1 complex. These observations suggest that interactions between adjacent methyl-lysine and phosphoserine side chains do not by themselves provide a binary switch in the H3-HP1 system, but arginine-phosphoserine interactions, which occur in both histones and nonhistone proteins in the context of a conserved RKS motif, are likely to serve a key regulatory function.},
author = {Papamokos, George V and Tziatzos, George and Papageorgiou, Dimitrios G and Georgatos, Spyros D and Politou, Anastasia S and Kaxiras, Efthimios},
doi = {10.1016/j.bpj.2012.03.030},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ack\_ff.pdf:pdf},
issn = {1542-0086},
journal = {Biophysical journal},
keywords = {Amino Acid Motifs,Chromatin,Chromatin: chemistry,Chromatin: metabolism,Chromosomal Proteins, Non-Histone,Chromosomal Proteins, Non-Histone: chemistry,Chromosomal Proteins, Non-Histone: metabolism,Histones,Histones: chemistry,Histones: metabolism,Hydrogen Bonding,Molecular Dynamics Simulation,Phosphorylation,Protein Binding,Serine,Serine: metabolism},
month = apr,
number = {8},
pages = {1926--33},
pmid = {22768949},
title = {{Structural role of RKS motifs in chromatin interactions: a molecular dynamics study of HP1 bound to a variably modified histone tail.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3328719\&tool=pmcentrez\&rendertype=abstract},
volume = {102},
year = {2012}
}
@article{Papamokos2012a,
abstract = {The current understanding of epigenetic signaling assigns a central role to post-translational modifications that occur in the histone tails. In this context, it has been proposed that methylation of K9 and phosphorylation of S10 in the tail of histone H3 represent a binary switch that controls its reversible association to heterochromatin protein 1 (HP1). To test this hypothesis, we performed a comprehensive molecular dynamics study in which we analyzed a crystallographically defined complex that involves the HP1 chromodomain and an H3 tail peptide. Microsecond-long simulations show that the binding of the trimethylated K9 H3 peptide in the aromatic cage of HP1 is only slightly affected by S10 phosphorylation, because the modified K9 and S10 do not interact directly with one another. Instead, the phosphate group of S10 seems to form a persistent intramolecular salt bridge with R8, an interaction that can provoke a major structural change and alter the hydrogen-bonding regime in the H3-HP1 complex. These observations suggest that interactions between adjacent methyl-lysine and phosphoserine side chains do not by themselves provide a binary switch in the H3-HP1 system, but arginine-phosphoserine interactions, which occur in both histones and nonhistone proteins in the context of a conserved RKS motif, are likely to serve a key regulatory function.},
author = {Papamokos, George V and Tziatzos, George and Papageorgiou, Dimitrios G and Georgatos, Spyros D and Politou, Anastasia S and Kaxiras, Efthimios},
doi = {10.1016/j.bpj.2012.03.030},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1-s2.0-S0006349512003414-main.pdf:pdf},
issn = {1542-0086},
journal = {Biophysical journal},
keywords = {Amino Acid Motifs,Chromatin,Chromatin: chemistry,Chromatin: metabolism,Chromosomal Proteins, Non-Histone,Chromosomal Proteins, Non-Histone: chemistry,Chromosomal Proteins, Non-Histone: metabolism,Histones,Histones: chemistry,Histones: metabolism,Hydrogen Bonding,Molecular Dynamics Simulation,Phosphorylation,Protein Binding,Serine,Serine: metabolism},
month = apr,
number = {8},
pages = {1926--33},
pmid = {22768949},
publisher = {Biophysical Society},
title = {{Structural role of RKS motifs in chromatin interactions: a molecular dynamics study of HP1 bound to a variably modified histone tail.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3328719\&tool=pmcentrez\&rendertype=abstract},
volume = {102},
year = {2012}
}
@article{Rotili2012,
author = {Rotili, Dante and Tarantino, Domenico and Nebbioso, Angela and Paolini, Chantal and Huidobro, Covadonga and Lara, Ester and Mellini, Paolo and Lenoci, Alessia and Pezzi, Riccardo and Botta, Giorgia and Lahtela-kakkonen, Maija and Poso, Antti and Steinku, Christian and Gallinari, Paola and Maria, Ruggero De and Fraga, Mario and Esteller, Manel and Altucci, Lucia and Mai, Antonello and Pasteur, Istituto and Cenci, Fondazione and Sapienza, La and Moro, P A},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm3011614.pdf:pdf},
journal = {Journal of medicinal Chemistry},
pages = {10937--10947},
title = {{Discovery of Salermide-Related Sirtuin Inhibitors: Binding Mode Studies and Antiproliferative Effects in Cancer Cells Including Cancer Stem Cells}},
url = {http://pubs.acs.org/doi/abs/10.1021/jm3011614},
volume = {55},
year = {2012}
}
@article{Suenaga2012,
abstract = {Virtual compound screening using molecular docking is widely used in the discovery of new lead compounds for drug design. However, the docking scores are not sufficiently precise to represent the protein-ligand binding affinity. Here, we developed an efficient computational method for calculating protein-ligand binding affinity, which is based on molecular mechanics generalized Born/surface area (MM-GBSA) calculations and Jarzynski identity. Jarzynski identity is an exact relation between free energy differences and the work done through non-equilibrium process, and MM-GBSA is a semimacroscopic approach to calculate the potential energy. To calculate the work distribution when a ligand is pulled out of its binding site, multiple protein-ligand conformations are randomly generated as an alternative to performing an explicit single-molecule pulling simulation. We assessed the new method, multiple random conformation/MM-GBSA (MRC-MMGBSA), by evaluating ligand-binding affinities (scores) for four target proteins, and comparing these scores with experimental data. The calculated scores were qualitatively in good agreement with the experimental binding affinities, and the optimal docking structure could be determined by ranking the scores of the multiple docking poses obtained by the molecular docking process. Furthermore, the scores showed a strong linear response to experimental binding free energies, so that the free energy difference of the ligand binding ($\Delta$$\Delta$G) could be calculated by linear scaling of the scores. The error of calculated $\Delta$$\Delta$G was within ≈ ± 1.5 kcal.mol(-1) of the experimental values. Particularly, in the case of flexible target proteins, the MRC-MMGBSA scores were more effective in ranking ligands than those generated by the MM-GBSA method using a single protein-ligand conformation. The results suggest that, owing to its lower computational costs and greater accuracy, the MRC-MMGBSA offers efficient means to rank the ligands, in the post-docking process, according to their binding affinities, and to compare these directly with the experimental values.},
author = {Suenaga, Atsushi and Okimoto, Noriaki and Hirano, Yoshinori and Fukui, Kazuhiko},
doi = {10.1371/journal.pone.0042846},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/journal.pone.0042846.pdf:pdf},
issn = {1932-6203},
journal = {PloS one},
keywords = {Ligands,Molecular Conformation,Protein Binding,Proteins,Proteins: chemistry,Proteins: metabolism,Thermodynamics},
month = jan,
number = {8},
pages = {e42846},
pmid = {22916168},
title = {{An efficient computational method for calculating ligand binding affinities.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3423425\&tool=pmcentrez\&rendertype=abstract},
volume = {7},
year = {2012}
}
@article{Szczepankiewicz2012,
abstract = {Carba-NAD is a synthetic compound identical to NAD except for one substitution, where an oxygen atom adjacent to the anomeric linkage bearing nicotinamide is replaced with a methylene group. Because it is inert in nicotinamide displacement reactions, carba-NAD is an unreactive substrate analogue for NAD-consuming enzymes. SIRT3 and SIRT5 are NAD-consuming enzymes that are potential therapeutic targets for the treatment of metabolic diseases and cancers. We report an improved carba-NAD synthesis, including a pyrophosphate coupling method that proceeds in approximately 60\% yield. We also disclose the X-ray crystal structures of the ternary complexes of SIRT3 and SIRT5 bound to a peptide substrate and carba-NAD. These X-ray crystal structures provide critical snapshots of the mechanism by which human sirtuins function as protein deacylation catalysts.},
author = {Szczepankiewicz, Bruce G and Dai, Han and Koppetsch, Karsten J and Qian, Dongming and Jiang, Fan and Mao, Cheney and Perni, Robert B},
doi = {10.1021/jo301067e},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jo301067e.pdf:pdf},
issn = {1520-6904},
journal = {The Journal of organic chemistry},
keywords = {Carbasugars,Carbasugars: chemical synthesis,Carbasugars: chemistry,Carbasugars: metabolism,Crystallography, X-Ray,Humans,Models, Molecular,Molecular Structure,NAD,NAD: chemical synthesis,NAD: chemistry,NAD: metabolism,Sirtuin 3,Sirtuin 3: chemistry,Sirtuin 3: metabolism,Sirtuins,Sirtuins: chemistry,Sirtuins: metabolism,Stereoisomerism},
month = sep,
number = {17},
pages = {7319--29},
pmid = {22849721},
title = {{Synthesis of carba-NAD and the structures of its ternary complexes with SIRT3 and SIRT5.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/22849721},
volume = {77},
year = {2012}
}
@article{Ahmed2013,
author = {Ahmed, M and Bird, Stefanie and Wang, Feng and Palombo, EA},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/1305.3691.pdf:pdf},
journal = {arXiv preprint arXiv:1305.3691},
keywords = {corresponding author},
title = {{In silico investigation of lactone and thiolactone inhibitors in bacterial quorum sensing using molecular modeling}},
url = {http://arxiv.org/abs/1305.3691},
year = {2013}
}
@article{Disch2013,
abstract = {The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.},
author = {Disch, Jeremy S and Evindar, Ghotas and Chiu, Cynthia H and Blum, Charles a and Dai, Han and Jin, Lei and Schuman, Eli and Lind, Kenneth E and Belyanskaya, Svetlana L and Deng, Jianghe and Coppo, Frank and Aquilani, Leah and Graybill, Todd L and Cuozzo, John W and Lavu, Siva and Mao, Cheney and Vlasuk, George P and Perni, Robert B},
doi = {10.1021/jm400204k},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm400204k.pdf:pdf},
issn = {1520-4804},
journal = {Journal of medicinal chemistry},
keywords = {Drug Discovery,Humans,Models, Molecular,Protein Conformation,Pyrimidines,Pyrimidines: chemistry,Pyrimidines: pharmacology,Sirtuin 1,Sirtuin 1: antagonists \& inhibitors,Sirtuin 1: chemistry,Sirtuin 2,Sirtuin 2: antagonists \& inhibitors,Sirtuin 2: chemistry,Sirtuin 3,Sirtuin 3: antagonists \& inhibitors,Sirtuin 3: chemistry,Sirtuins,Sirtuins: antagonists \& inhibitors,Sirtuins: chemistry},
month = may,
number = {9},
pages = {3666--79},
pmid = {23570514},
title = {{Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23570514},
volume = {56},
year = {2013}
}
@article{Elokely2013,
abstract = {Computational tools are essential in the drug design process, especially in order to take advantage of the increasing numbers of solved X-ray and NMR protein-ligand structures. Nowadays, molecular docking methods are routinely used for prediction of protein-ligand interactions and to aid in selecting potent molecules as a part of virtual screening of large databases. The improvements and advances in computational capacity in the past decade have allowed for further developments in molecular docking algorithms to address more complicated aspects such as protein flexibility. The effects of incorporation of active site water molecules and implicit or explicit solvation of the binding site are other relevant issues to be addressed in the docking procedures. Using the right docking algorithm at the right stage of virtual screening is most important. We report a staged study to address the effects of various aspects of protein flexibility and inclusion of active site water molecules on docking effectiveness to retrieve (and to be able to predict) correct ligand poses and to rank docked ligands in relation to their biological activity for CHK1, ERK2, LpxC, and UPA. We generated multiple conformers for the ligand and compared different docking algorithms that use a variety of approaches to protein flexibility, including rigid receptor, soft receptor, flexible side chains, induced fit, and multiple structure algorithms. Docking accuracy varied from 1\% to 84\%, demonstrating that the choice of method is important.},
author = {Elokely, Khaled M and Doerksen, Robert J},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ci400040d.pdf:pdf},
journal = {Journal of chemical information and modeling},
pages = {1934--1945},
title = {{Docking Challenge: Protein Sampling and Molecular Docking Performance.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23530568},
volume = {53},
year = {2013}
}
@article{Gertz2013,
abstract = {Sirtuins are protein deacetylases regulating metabolism and stress responses. The seven human Sirtuins (Sirt1-7) are attractive drug targets, but Sirtuin inhibition mechanisms are mostly unidentified. We report the molecular mechanism of Sirtuin inhibition by 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (Ex-527). Inhibitor binding to potently inhibited Sirt1 and Thermotoga maritima Sir2 and to moderately inhibited Sirt3 requires NAD(+), alone or together with acetylpeptide. Crystal structures of several Sirtuin inhibitor complexes show that Ex-527 occupies the nicotinamide site and a neighboring pocket and contacts the ribose of NAD(+) or of the coproduct 2'-O-acetyl-ADP ribose. Complex structures with native alkylimidate and thio-analog support its catalytic relevance and show, together with biochemical assays, that only the coproduct complex is relevant for inhibition by Ex-527, which stabilizes the closed enzyme conformation preventing product release. Ex-527 inhibition thus exploits Sirtuin catalysis, and kinetic isoform differences explain its selectivity. Our results provide insights in Sirtuin catalysis and inhibition with important implications for drug development.},
author = {Gertz, Melanie and Fischer, Frank},
doi = {10.1073/pnas.1303628110/-/DCSupplemental.www.pnas.org/cgi/doi/10.1073/pnas.1303628110},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/PNAS-2013-Gertz-E2772-81.pdf:pdf},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = {30},
pages = {E2772--81},
title = {{Ex-527 inhibits Sirtuins by exploiting their unique NAD+-dependent deacetylation mechanism}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23840057 http://www.pnas.org/content/110/30/E2772.short},
volume = {110},
year = {2013}
}
@article{Greenidge2013,
abstract = {We validate an automated implementation of a combined Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method (VSGB 2.0 energy model) on a large and diverse selection of protein-ligand complexes (855 complexes). Although this data set is diverse with respect to both protein families and ligands, after carefully removing flawed structures, a significant correlation (R(2) = 0.63) between calculated and experimental binding affinities is obtained. Consistent explanations for "outlier" complexes are found. Visual analysis of the crystal structures and recourse to the original literature reveal that neglect of explicit solvent, ligand strain, and entropy contribute to the under- and overestimation of computed affinities. The limits of the Molecular Mechanics/Implicit Solvent approach to accurately estimate protein-ligand binding affinities is discussed as is the influence of the quality of protein-ligand complexes on computed free energy binding values.},
author = {Greenidge, Paulette a and Kramer, Christian and Mozziconacci, Jean-Christophe and Wolf, Romain M},
doi = {10.1021/ci300425v},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ci300425v.pdf:pdf},
issn = {1549-960X},
journal = {Journal of chemical information and modeling},
keywords = {Databases, Protein,Entropy,HIV Protease,HIV Protease: metabolism,Hydrogen Bonding,Ligands,Models, Molecular,Oligopeptides,Oligopeptides: metabolism,Protein Conformation,Proteins,Proteins: chemistry,Proteins: metabolism,Surface Properties,Thermodynamics,Water,Water: chemistry},
month = jan,
number = {1},
pages = {201--9},
pmid = {23268595},
title = {{MM/GBSA binding energy prediction on the PDBbind data set: successes, failures, and directions for further improvement.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23268595},
volume = {53},
year = {2013}
}
@article{Hubbard2013,
author = {Hubbard, BP and Gomes, AP and Dai, H and Li, J},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/Hubbard-2013-Evidence for a Commo.pdf:pdf},
journal = {Science},
pages = {1216--1219},
title = {{Evidence for a common mechanism of SIRT1 regulation by allosteric activators}},
url = {http://www.sciencemag.org/content/339/6124/1216.short},
volume = {339},
year = {2013}
}
@article{Nguyen2013,
abstract = {Sirtuins are NAD(+)-dependent protein deacetylases that regulate metabolism and aging processes and are considered to be attractive therapeutic targets. Most available sirtuin modulators are little understood mechanistically, hindering their improvement. SRT1720 was initially described as an activator of human Sirt1, but it also potently inhibits human Sirt3. Here, the molecular mechanism of the inhibition of Sirt3 by SRT1720 is described. A crystal structure of Sirt3 in complex with SRT1720 and an NAD(+) analogue reveals that the compound partially occupies the acetyl-Lys binding site, thus explaining the reported competition with the peptide substrate. The compound packs against a hydrophobic protein patch and binds with its opposite surface to the NAD(+) nicotinamide, resulting in an exceptionally tight sandwich-like interaction. The observed arrangement rationalizes the uncompetitive inhibition with NAD(+), and binding measurements confirm that the nicotinamide moiety of NAD(+) supports inhibitor binding. Consistently, no inhibitor is bound in a second crystal structure of Sirt3 that was solved complexed with ADP-ribose and crystallized in the presence of SRT1720. These results reveal a novel sirtuin inhibitor binding site and mechanism, and provide a structural basis for compound improvement.},
author = {Nguyen, GTT and Schaefer, Susanne},
doi = {10.1107/S0907444913015448},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/wd5219.pdf:pdf},
issn = {1399-0047},
journal = {Acta Crystallographica Section D Biological Crystallography},
month = aug,
number = {Pt 8},
pages = {1423--32},
pmid = {23897466},
publisher = {International Union of Crystallography},
title = {{Structures of human sirtuin 3 complexes with ADP-ribose and with carba-NAD+ and SRT1720: binding details and inhibition mechanism}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/23897466 http://scripts.iucr.org/cgi-bin/paper\_yard?wd5219},
volume = {69},
year = {2013}
}
@article{Sakkiah2013,
abstract = {The ability to identify the site of a protein that can bind with high affinity to small, drug-like compounds has been an important goal in drug design. Sirtuin 2 (SIRT2), histone deacetylase protein family, plays a central role in the regulation of various pathways. Hence, identification of drug for SIRT2 has attracted great interest in the drug discovery community. To elucidate the molecular basis of the small molecules interactions to inhibit the SIRT2 function we employed the molecular docking, molecular dynamics simulations, and the molecular mechanism Poisson-Boltzmann/surface area (MM-PBSA) calculations. Five well know inhibitors such as suramin, mol-6, sirtinol, 67, and nf675 were selected to establish the nature of the binding mode of the inhibitors in the SIRT2 active site. The molecular docking and dynamics simulations results revealed that the hydrogen bonds between Arg97 and Gln167 are crucial to inhibit the function of SIRT2. In addition, the MM-PBSA calculations revealed that binding of inhibitors to SIRT2 is mainly driven by van der Waals/non-polar interactions. Although the five inhibitors are very different in structure, shape, and electrostatic potential, they are able to fit in the same binding pocket. These findings from this study provide insights to elucidate the binding pattern of SIRT2 inhibitors and help in the rational structure-based design of novel SIRT2 inhibitors with improved potency and better resistance profile.},
author = {Sakkiah, Sugunadevi and Arooj, Mahreen and Kumar, Manian Rajesh and Eom, Soo Hyun and Lee, Keun Woo},
doi = {10.1371/journal.pone.0051429},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/journal.pone.0051429.pdf:pdf},
issn = {1932-6203},
journal = {PloS one},
keywords = {Binding Sites,Catalytic Domain,Drug Discovery,Histone Deacetylase Inhibitors,Histone Deacetylase Inhibitors: chemistry,Humans,Hydrogen Bonding,Molecular Docking Simulation,Molecular Dynamics Simulation,Protein Conformation,Sirtuin 2,Sirtuin 2: antagonists \& inhibitors,Sirtuin 2: chemistry,Sirtuin 2: ultrastructure,Structure-Activity Relationship,Thermodynamics},
month = jan,
number = {1},
pages = {e51429},
pmid = {23382805},
title = {{Identification of inhibitor binding site in human sirtuin 2 using molecular docking and dynamics simulations.}},
url = {http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3557295\&tool=pmcentrez\&rendertype=abstract},
volume = {8},
year = {2013}
}
@article{Salo2013,
author = {Salo, Heikki S and Laitinen, Tuomo and Poso, Antti and Jarho, Elina and Lahtela-kakkonen, Maija},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/ac.els-cdn.com\_S0960894X13003491\_1-s2.0-S0960894X13003491-main.pdf:pdf},
journal = {Bioorganic \& Medicinal Chemistry Letters},
pages = {2990--2995},
title = {{Identification of novel SIRT3 inhibitor scaffolds by virtual screening}},
volume = {23},
year = {2013}
}
@article{Zhao2013,
author = {Zhao, Xun and Allison, Dagart and Condon, Bradley},
file = {:C$\backslash$:/Users/plin/Documents/SIRT/jm301431y.pdf:pdf},
journal = {Journal of Medicinal Chemistry},
pages = {963--969},
title = {{The 2.5 \AA crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD+) and an indole (EX527 analogue) reveals a novel mechanism}},
url = {http://pubs.acs.org/doi/full/10.1021/jm301431y},
volume = {56},
year = {2013}
}