Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes.

A novel scoring function to estimate protein-ligand binding affinities has been developed and implemented as the Glide 4.0 XP scoring function and docking protocol. In addition to unique water desolvation energy terms, protein-ligand structural motifs leading to enhanced binding affinity are included: (1) hydrophobic enclosure where groups of lipophilic ligand atoms are enclosed on opposite faces by lipophilic protein atoms, (2) neutral-neutral single or correlated hydrogen bonds in a hydrophobically enclosed environment, and (3) five categories of charged-charged hydrogen bonds. The XP scoring function and docking protocol have been developed to reproduce experimental binding affinities for a set of 198 complexes (RMSDs of 2.26 and 1.73 kcal/mol over all and well-docked ligands, respectively) and to yield quality enrichments for a set of fifteen screens of pharmaceutical importance. Enrichment results demonstrate the importance of the novel XP molecular recognition and water scoring in separating active and inactive ligands and avoiding false positives.

[1]  T. Tezuka,et al.  THROMBIN INHIBITORS. 2. AMIDE DERIVATIVES OF Nα-SUBSTITUTED L-ARGININE , 1981 .

[2]  B. Matthews,et al.  Binding of N-carboxymethyl dipeptide inhibitors to thermolysin determined by X-ray crystallography: a novel class of transition-state analogues for zinc peptidases. , 1984, Biochemistry.

[3]  R. Kikumoto,et al.  Selective inhibition of thrombin by (2R,4R)-4-methyl-1-[N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl++ +) sulfonyl]-l-arginyl)]-2-piperidinecarboxylic acid. , 1984, Biochemistry.

[4]  J. Andrew McCammon,et al.  The structure of liquid water at an extended hydrophobic surface , 1984 .

[5]  H M Holden,et al.  Structures of two thermolysin-inhibitor complexes that differ by a single hydrogen bond. , 1987, Science.

[6]  H M Holden,et al.  Slow- and fast-binding inhibitors of thermolysin display different modes of binding: crystallographic analysis of extended phosphonamidate transition-state analogues. , 1989, Biochemistry.

[7]  P. Bartlett,et al.  Possible role for water dissociation in the slow binding of phosphorus-containing transition-state-analogue inhibitors of thermolysin. , 1987, Biochemistry.

[8]  B Honig,et al.  Reconciling the magnitude of the microscopic and macroscopic hydrophobic effects. , 1991, Science.

[9]  J H Miller,et al.  Delineating the pharmacophoric elements of huperzine A: importance of the unsaturated three-carbon bridge to its AChE inhibitory activity. , 1991, Journal of medicinal chemistry.

[10]  K. Sharp,et al.  Protein folding and association: Insights from the interfacial and thermodynamic properties of hydrocarbons , 1991, Proteins.

[11]  W. Schäfer,et al.  Selective non-nucleoside HIV-1 reverse transcriptase inhibitors. New 2,3-dihydrothiazolo[2,3-a]isoindol-5(9bH)-ones and related compounds with anti-HIV-1 activity. , 1993, Journal of medicinal chemistry.

[12]  L. Kuo,et al.  Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases. , 1996, The Journal of biological chemistry.

[13]  B. Tidor,et al.  Do salt bridges stabilize proteins? A continuum electrostatic analysis , 1994, Protein science : a publication of the Protein Society.

[14]  Peter J. Rossky,et al.  A comparison of the structure and dynamics of liquid water at hydrophobic and hydrophilic surfaces—a molecular dynamics simulation study , 1994 .

[15]  D. R. Holland,et al.  Inhibition of thermolysin and neutral endopeptidase 24.11 by a novel glutaramide derivative: X-ray structure determination of the thermolysin-inhibitor complex. , 1994, Biochemistry.

[16]  Hans-Joachim Böhm,et al.  The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure , 1994, J. Comput. Aided Mol. Des..

[17]  I D Kuntz,et al.  Docking analysis of a series of benzylamino acetylcholinesterase inhibitors with a phthalimide, benzoyl, or indanone moiety. , 1994, Journal of medicinal chemistry.

[18]  R. Sauer,et al.  Contributions of a hydrogen bond/salt bridge network to the stability of secondary and tertiary structure in λ repressor , 1994, Protein science : a publication of the Protein Society.

[19]  B. Berne,et al.  Molecular Dynamics Study of the Dependence of Water Solvation Free Energy on Solute Curvature and Surface Area , 1995 .

[20]  Gennady M Verkhivker,et al.  Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. , 1995, Chemistry & biology.

[21]  Anders Wallqvist,et al.  Computer Simulation of Hydrophobic Hydration Forces on Stacked Plates at Short Range , 1995 .

[22]  R. Sauer,et al.  Are buried salt bridges important for protein stability and conformational specificity? , 1995, Nature Structural Biology.

[23]  H Brandstetter,et al.  Enzyme flexibility, solvent and 'weak' interactions characterize thrombin-ligand interactions: implications for drug design. , 1996, Structure.

[24]  J. C. Dyason,et al.  A study of the active site of influenza virus sialidase: an approach to the rational design of novel anti-influenza drugs. , 1996, Journal of medicinal chemistry.

[25]  K D Stewart,et al.  A novel, picomolar inhibitor of human immunodeficiency virus type 1 protease. , 1996, Journal of medicinal chemistry.

[26]  J. Boehm,et al.  1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency. , 1996, Journal of medicinal chemistry.

[27]  C. Koboldt,et al.  Diarylspiro[2.4]heptenes as orally active, highly selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationships. , 1996, Journal of medicinal chemistry.

[28]  J H Matthews,et al.  Crystal structures of thrombin with thiazole-containing inhibitors: probes of the S1' binding site. , 1996, Biophysical journal.

[29]  Chong-Hwan Chang,et al.  Cyclic HIV protease inhibitors: synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. , 1996, Journal of medicinal chemistry.

[30]  M. Doyle,et al.  Human immunodeficiency virus protease ligand specificity conferred by residues outside of the active site cavity. , 1996, Biochemistry.

[31]  Novel Terphenyls as Selective Cyclooxygenase‐2 Inhibitors and Orally Active anti‐Inflammatory Agents. , 1996 .

[32]  Thomas Lengauer,et al.  A fast flexible docking method using an incremental construction algorithm. , 1996, Journal of molecular biology.

[33]  G. V. Paolini,et al.  Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding affinity of ligands in receptor complexes , 1997, J. Comput. Aided Mol. Des..

[34]  P Willett,et al.  Development and validation of a genetic algorithm for flexible docking. , 1997, Journal of molecular biology.

[35]  J. Simard,et al.  (S)-(+)-4-[7-(2,2-dimethyl-1-oxopropoxy)-4-methyl-2-[4-[2-(1-piperidinyl)-ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl 2,2-dimethylpropanoate (EM-800): a highly potent, specific, and orally active nonsteroidal antiestrogen. , 1997, Journal of medicinal chemistry.

[36]  L. Tong,et al.  A highly specific inhibitor of human p38 MAP kinase binds in the ATP pocket , 1997, Nature Structural Biology.

[37]  C. Koboldt,et al.  1,2-Diarylimidazoles as potent, cyclooxygenase-2 selective, and orally active antiinflammatory agents. , 1997, Journal of medicinal chemistry.

[38]  W G Laver,et al.  Design and synthesis of benzoic acid derivatives as influenza neuraminidase inhibitors using structure-based drug design. , 1997, Journal of medicinal chemistry.

[39]  J. Boehm,et al.  Regulation of stress-induced cytokine production by pyridinylimidazoles; inhibition of CSBP kinase. , 1997, Bioorganic & medicinal chemistry.

[40]  N. Chirgadze,et al.  The crystal structure of human α‐thrombin complexed with LY178550, a nonpeptidyl, active site‐directed inhibitor , 1997, Protein science : a publication of the Protein Society.

[41]  F. Peng.  Structure and anti-acetylcholinesterase activity of 4 alpha-(hydroxymethyl)-4 alpha-demethylterritrem B. , 1997, Journal of natural products.

[42]  W. M. Sanders,et al.  Synthesis, evaluation, and crystallographic analysis of L-371,912: A potent and selective active-site thrombin inhibitor. , 1997 .

[43]  W G Laver,et al.  Guanidinobenzoic acid inhibitors of influenza virus neuraminidase. , 1997, Journal of molecular biology.

[44]  W G Laver,et al.  Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. , 1997, Journal of the American Chemical Society.

[45]  M. Bolognesi,et al.  Human alpha-thrombin inhibition by the highly selective compounds N-ethoxycarbonyl-D-Phe-Pro-alpha-azaLys p-nitrophenyl ester and N-carbobenzoxy-Pro-alpha-azaLys p-nitrophenyl ester: a kinetic, thermodynamic and X-ray crystallographic study. , 1997, Journal of molecular biology.

[46]  Sung-Hou Kim,et al.  Structural basis for chemical inhibition of human blood coagulation factor Xa. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[47]  D. Thompson,et al.  Discovery and preclinical pharmacology of a novel, potent, nonsteroidal estrogen receptor agonist/antagonist, CP-336156, a diaryltetrahydronaphthalene. , 1998, Journal of medicinal chemistry.

[48]  Potent inhibitors of the MAP kinase p38. , 1998, Bioorganic & medicinal chemistry letters.

[49]  N. R. Taylor.  Dihydropyrancarboxamides Related to Zanamivir: A New Series of Inhibitors of Influenza Virus Sialidases. Part 2. Crystallographic and Molecular Modeling Study of Complexes of 4-Amino-4H-pyran-6-carboxamides and Sialidase from Influenza Virus Types A and B. , 1998 .

[50]  Robert M. Stroud,et al.  Design of potent selective zinc-mediated serine protease inhibitors , 1998, Nature.

[51]  C. Ehrhardt,et al.  Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors. , 1998, Journal of medicinal chemistry.

[52]  E. Goldsmith,et al.  Structural basis of inhibitor selectivity in MAP kinases. , 1998, Structure.

[53]  M L Bolognesi,et al.  Acetylcholinesterase noncovalent inhibitors based on a polyamine backbone for potential use against Alzheimer's disease. , 1998, Journal of medicinal chemistry.

[54]  M. Maccoss,et al.  Pyrroles and other heterocycles as inhibitors of p38 kinase. , 1998, Bioorganic & medicinal chemistry letters.

[55]  J. Spurlino,et al.  Structural analysis of thrombin complexed with potent inhibitors incorporating a phenyl group as a peptide mimetic and aminopyridines as guanidine substitutes. , 1998, Journal of medicinal chemistry.

[56]  R. Sidwell,et al.  Characterization of Human Influenza Virus Variants Selected In Vitro in the Presence of the Neuraminidase Inhibitor GS 4071 , 1998, Antimicrobial Agents and Chemotherapy.

[57]  R. Neidlein,et al.  Diarylsulfonamides as selective, non-peptidic thrombin inhibitors. , 1998, Bioorganic & medicinal chemistry letters.

[58]  David S. Goodsell,et al.  Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function , 1998, J. Comput. Chem..

[59]  Peter J. Rossky,et al.  Surface topography dependence of biomolecular hydrophobic hydration , 1998, Nature.

[60]  A. Tulinsky,et al.  Structure of Thrombin Inhibited by Aeruginosin 298-A from a Blue-Green Alga , 1998 .

[61]  D I Stuart,et al.  Crystal structures of HIV-1 reverse transcriptase in complex with carboxanilide derivatives. , 1998, Biochemistry.

[62]  Paul W Smith,et al.  Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase. , 1998, Structure.

[63]  P. Charifson,et al.  N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 3. Structure-activity relationship and optimization of the N-aryl substituent. , 1998, Journal of medicinal chemistry.

[64]  Hans-Joachim Böhm,et al.  Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs , 1998, J. Comput. Aided Mol. Des..

[65]  Thomas A. Halgren.  MMFF VI. MMFF94s option for energy minimization studies , 1999, J. Comput. Chem..

[66]  Y. Martin,et al.  A general and fast scoring function for protein-ligand interactions: a simplified potential approach. , 1999, Journal of medicinal chemistry.

[67]  M. Gilson,et al.  Strength of Solvent-Exposed Salt-Bridges† , 1999 .

[68]  G. Air,et al.  Potent inhibition of influenza sialidase by a benzoic acid containing a 2-pyrrolidinone substituent. , 1999, Journal of medicinal chemistry.

[69]  D. Chandler,et al.  Hydrophobicity at Small and Large Length Scales , 1999 .

[70]  M. Morrissey,et al.  Discovery of N‐[2‐[5‐[Amino(imino)methyl]‐2‐hydroxyphenoxy]‐3,5‐difluoro‐6‐ [3‐(4,5‐dihydro‐1‐methyl‐1H‐imidazol‐2‐yl)phenoxy]pyridin‐4‐yl] ‐N‐methylglycine (ZK‐807834): A Potent, Selective, and Orally Active Inhibitor of the Blood Coagulation Enzyme Factor Xa. , 1999 .

[71]  Y. Jang,et al.  Protopine from Corydalis ternata has anticholinesterase and antiamnesic activities. , 1999, Planta medica.

[72]  T. Willson,et al.  The PPARs: from orphan receptors to drug discovery. , 2000, Journal of medicinal chemistry.

[73]  D. Lane,et al.  Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. , 2000, Current medicinal chemistry.

[74]  B. Zhu,et al.  Chapter 9. Factor Xa inhibitors: Recent advances in anticoagulant agents , 2000 .

[75]  E. Novellino,et al.  Structure-based design, synthesis, and biological evaluation of novel pyrrolyl aryl sulfones: HIV-1 non-nucleoside reverse transcriptase inhibitors active at nanomolar concentrations. , 2000, Journal of medicinal chemistry.

[76]  D. Rognan,et al.  Protein-based virtual screening of chemical databases. 1. Evaluation of different docking/scoring combinations. , 2000, Journal of medicinal chemistry.

[77]  F. J. Luque,et al.  New tacrine-huperzine A hybrids (huprines): highly potent tight-binding acetylcholinesterase inhibitors of interest for the treatment of Alzheimer's disease. , 2000, Journal of medicinal chemistry.

[78]  A. Cavalli,et al.  SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues. , 2000, Journal of medicinal chemistry.

[79]  C. Guillou,et al.  Potent acetylcholinesterase inhibitors: design, synthesis and structure-activity relationships of alkylene linked bis-galanthamine and galanthamine-galanthaminium salts. , 2000, Bioorganic & medicinal chemistry letters.

[80]  G L Trainor,et al.  Cyclin-dependent kinase inhibitors: useful targets in cell cycle regulation. , 2000, Journal of medicinal chemistry.

[81]  S Diamond,et al.  Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors. , 2000, Journal of medicinal chemistry.

[82]  Structure of thrombin complexed with selective non-electrophilic inhibitors having cyclohexyl moieties at P1. , 2000, Acta crystallographica. Section D, Biological crystallography.

[83]  R. Fuchs-Young,et al.  Preclinical Evidence for Therapeutic Efficacy of Selective Estrogen receptor Modulators for Uterine Leiomyoma , 2000, The Journal of the Society for Gynecologic Investigation: JSGI.

[84]  SAR of 4-hydroxypiperidine and hydroxyalkyl substituted heterocycles as novel p38 map kinase inhibitors. , 2000, Bioorganic & medicinal chemistry letters.

[85]  S. Hubbard,et al.  Identification of substituted 3-[(4,5,6, 7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases. , 2000, Journal of medicinal chemistry.

[86]  J Feixas,et al.  Synthesis and biological evaluation of 3,4-diaryloxazolones: A new class of orally active cyclooxygenase-2 inhibitors. , 2000, Journal of medicinal chemistry.

[87]  M. Zhang,et al.  The crystal structures of human α‐thrombin complexed with active site‐directed diamino benzo[b] thiophene derivatives: A binding mode for a structurally novel class of inhibitors , 2008, Protein science : a publication of the Protein Society.

[88]  D. Boschelli,et al.  Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclin-dependent kinases. , 2000, Journal of medicinal chemistry.

[89]  S. Swaney,et al.  Novel 1,5-diphenylpyrazole nonnucleoside HIV-1 reverse transcriptase inhibitors with enhanced activity versus the delavirdine-resistant P236L mutant: lead identification and SAR of 3- and 4-substituted derivatives. , 2000, Journal of medicinal chemistry.

[90]  G. Klebe,et al.  Knowledge-based scoring function to predict protein-ligand interactions. , 2000, Journal of molecular biology.

[91]  J. Koča,et al.  Docking-based development of purine-like inhibitors of cyclin-dependent kinase-2. , 2000, Journal of medicinal chemistry.

[92]  E. Leahy,et al.  Optimization of a screening lead for factor VIIa/TF. , 2001, Bioorganic & medicinal chemistry letters.

[93]  J. Janc,et al.  A novel serine protease inhibition motif involving a multi-centered short hydrogen bonding network at the active site. , 2002, Journal of molecular biology.

[94]  E. Knaus,et al.  Design and synthesis of celecoxib and rofecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of sulfonamide and methylsulfonyl pharmacophores by an azido bioisostere. , 2001, Journal of medicinal chemistry.

[95]  S. Cox,et al.  Indenopyrazoles as novel cyclin dependent kinase (CDK) inhibitors. , 2001, Journal of medicinal chemistry.

[96]  D I Stuart,et al.  2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1. , 2001, Journal of medicinal chemistry.

[97]  Chris P. Miller,et al.  Design, synthesis, and preclinical characterization of novel, highly selective indole estrogens. , 2001, Journal of medicinal chemistry.

[98]  G. Hummer,et al.  Water conduction through the hydrophobic channel of a carbon nanotube , 2001, Nature.

[99]  P. A. Harris,et al.  Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis. , 2001, Journal of medicinal chemistry.

[100]  G Klebe,et al.  Factorising ligand affinity: a combined thermodynamic and crystallographic study of trypsin and thrombin inhibition. , 2001, Journal of molecular biology.

[101]  R. Pauwels,et al.  Evolution of anti-HIV drug candidates. Part 1: From α-Anilinophenylacetamide (α-APA) to imidoyl thiourea (ITU) , 2001 .

[102]  R. Pauwels,et al.  Evolution of anti-HIV drug candidates. Part 3: Diarylpyrimidine (DAPY) analogues. , 2001, Bioorganic & medicinal chemistry letters.

[103]  R. Pauwels,et al.  Evolution of anti-HIV drug candidates. Part 2: Diaryltriazine (DATA) analogues. , 2001, Bioorganic & medicinal chemistry letters.

[104]  H. Nar,et al.  Structural basis for inhibition promiscuity of dual specific thrombin and factor Xa blood coagulation inhibitors. , 2001, Structure.

[105]  Todd J. A. Ewing,et al.  DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases , 2001, J. Comput. Aided Mol. Des..

[106]  S. Roggo.  Inhibition of BACE, a promising approach to Alzheimer's disease therapy. , 2002, Current topics in medicinal chemistry.

[107]  J. Madwed,et al.  Pyrazole urea-based inhibitors of p38 MAP kinase: from lead compound to clinical candidate. , 2002, Journal of medicinal chemistry.

[108]  Antonio Entrena,et al.  Identification of novel cyclooxygenase-2 selective inhibitors using pharmacophore models. , 2002, Journal of medicinal chemistry.

[109]  Paul Greengard,et al.  Pharmacological inhibitors of cyclin-dependent kinases. , 2002, Trends in pharmacological sciences.

[110]  H. Matter,et al.  Structural classification of protein kinases using 3D molecular interaction field analysis of their ligand binding sites: target family landscapes. , 2002, Journal of medicinal chemistry.

[111]  Luhua Lai,et al.  Further development and validation of empirical scoring functions for structure-based binding affinity prediction , 2002, J. Comput. Aided Mol. Des..

[112]  Eric Therrien,et al.  Targeting thrombin and factor VIIa: design, synthesis, and inhibitory activity of functionally relevant indolizidinones. , 2002, Bioorganic & medicinal chemistry letters.

[113]  Pyrrolo[2,3-d]pyrimidines containing diverse N-7 substituents as potent inhibitors of Lck. , 2002, Bioorganic & medicinal chemistry letters.

[114]  H. Nar,et al.  Structure-based design of novel potent nonpeptide thrombin inhibitors. , 2002, Journal of medicinal chemistry.

[115]  Ingrid Pettersson,et al.  Novel Tricyclic-α-alkyloxyphenylpropionic Acids: Dual PPARα/γ Agonists with Hypolipidemic and Antidiabetic Activity , 2002 .

[116]  H. Fales,et al.  Oxidative Modifications of Kynostatin-272, a Potent Human Immunodeficiency Virus Type 1 Protease Inhibitor: Potential Mechanism for Altered Activity in Monocytes/Macrophages , 2002, Antimicrobial Agents and Chemotherapy.

[117]  Hans Matter,et al.  Design and quantitative structure-activity relationship of 3-amidinobenzyl-1H-indole-2-carboxamides as potent, nonchiral, and selective inhibitors of blood coagulation factor Xa. , 2002, Journal of medicinal chemistry.

[118]  B. Matthews,et al.  A model binding site for testing scoring functions in molecular docking. , 2002, Journal of molecular biology.

[119]  Punit Marathe,et al.  Discovery of aminothiazole inhibitors of cyclin-dependent kinase 2: synthesis, X-ray crystallographic analysis, and biological activities. , 2002, Journal of medicinal chemistry.

[120]  Ettore Novellino,et al.  Specific targeting of acetylcholinesterase and butyrylcholinesterase recognition sites. Rational design of novel, selective, and highly potent cholinesterase inhibitors. , 2003, Journal of medicinal chemistry.

[121]  Robert Leadley,et al.  Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand. , 2003, Journal of medicinal chemistry.

[122]  R. Kurumbail,et al.  Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex. , 2003, Journal of medicinal chemistry.

[123]  Werner Seitz,et al.  D-Phe-Pro-Arg type thrombin inhibitors: unexpected selectivity by modification of the P1 moiety. , 2003, Bioorganic & medicinal chemistry letters.

[124]  Chung F. Wong,et al.  A computational model of binding thermodynamics: the design of cyclin-dependent kinase 2 inhibitors. , 2003, Journal of medicinal chemistry.

[125]  M. Ihnat,et al.  Antiangiogenic and antitumor agents. Design, synthesis, and evaluation of novel 2-amino-4-(3-bromoanilino)-6-benzylsubstituted pyrrolo[2,3-d]pyrimidines as inhibitors of receptor tyrosine kinases. , 2003, Bioorganic & medicinal chemistry.

[126]  B. Tomczuk,et al.  Oxyguanidines: application to non-peptidic phenyl-based thrombin inhibitors. , 2003, Bioorganic & medicinal chemistry letters.

[127]  G. Desiraju,et al.  Design of EGFR kinase inhibitors: a ligand-based approach and its confirmation with structure-based studies. , 2003, Bioorganic & medicinal chemistry.

[128]  S. A. Watkins,et al.  Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors. , 2003, Journal of medicinal chemistry.

[129]  Paul Seiler,et al.  A fluorine scan of thrombin inhibitors to map the fluorophilicity/fluorophobicity of an enzyme active site: evidence for C-F...C=O interactions. , 2003, Angewandte Chemie.

[130]  Daniel R McMasters,et al.  Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines. , 2003, Journal of medicinal chemistry.

[131]  Renxiao Wang,et al.  Comparative evaluation of 11 scoring functions for molecular docking. , 2003, Journal of medicinal chemistry.

[132]  J. Madwed,et al.  Structure-activity relationships of the p38alpha MAP kinase inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796). , 2003, Journal of medicinal chemistry.

[133]  C. Pargellis,et al.  Thermal denaturation: a method to rank slow binding, high-affinity P38alpha MAP kinase inhibitors. , 2003, Journal of medicinal chemistry.

[134]  V. Andrisano,et al.  beta-Amyloid aggregation induced by human acetylcholinesterase: inhibition studies. , 2003, Biochemical pharmacology.

[135]  B. Gopalakrishnan,et al.  Synthesis and cyclooxygenase-2 inhibiting property of 1,5-diarylpyrazoles with substituted benzenesulfonamide moiety as pharmacophore: Preparation of sodium salt for injectable formulation. , 2003, Journal of medicinal chemistry.

[136]  R. Kurumbail,et al.  Synthesis and crystal structures of substituted benzenes and benzoquinones as tissue factor VIIa inhibitors. , 2003, Journal of medicinal chemistry.

[137]  D. Zaller,et al.  Structural basis for p38α MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity , 2003, Nature Structural Biology.

[138]  J. Janc,et al.  Elaborate manifold of short hydrogen bond arrays mediating binding of active site-directed serine protease inhibitors. , 2003, Journal of molecular biology.

[139]  Youwei Yan,et al.  Pharmacokinetic optimization of 3-amino-6-chloropyrazinone acetamide thrombin inhibitors. Implementation of P3 pyridine N-oxides to deliver an orally bioavailable series containing P1 N-benzylamides. , 2003, Bioorganic & medicinal chemistry letters.

[140]  Margaret S. Wu,et al.  (2R)-2-Ethylchromane-2-carboxylic Acids: Discovery of Novel PPARα/γ Dual Agonists as Antihyperglycemic and Hypolipidemic Agents , 2004 .

[141]  Novel Non‐covalent Thrombin Inhibitors Incorporating P1 4,5,6,7‐Tetrahydrobenzothiazole Arginine Side Chain Mimetics. , 2004 .

[142]  S. Hanessian,et al.  The N-acyloxyiminium ion aza-Prins route to octahydroindoles: total synthesis and structural confirmation of the antithrombotic marine natural product oscillarin. , 2004, Journal of the American Chemical Society.

[143]  Joseph B. Moon,et al.  Design and Synthesis of Hydroxyethylene-Based Peptidomimetic Inhibitors of Human β-Secretase , 2004 .

[144]  B. Tomczuk,et al.  Oxyguanidines. Part 2: Discovery of a novel orally active thrombin inhibitor through structure-based drug design and parallel synthesis. , 2004, Bioorganic & medicinal chemistry letters.

[145]  A. Carroll,et al.  Dysinosins B-D, inhibitors of factor VIIa and thrombin from the Australian sponge Lamellodysidea chlorea. , 2004, Journal of natural products.

[146]  Erik Verner,et al.  Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA). , 2004, Journal of Molecular Biology.

[147]  Hege S. Beard,et al.  Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. , 2004, Journal of medicinal chemistry.

[148]  Maria Kontoyianni,et al.  Evaluation of docking performance: comparative data on docking algorithms. , 2004, Journal of medicinal chemistry.

[149]  P. Charifson,et al.  Conformational analysis of drug-like molecules bound to proteins: an extensive study of ligand reorganization upon binding. , 2004, Journal of medicinal chemistry.

[150]  J. Mestan,et al.  AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. , 2004, Cancer research.

[151]  Novel p38 inhibitors with potent oral efficacy in several models of rheumatoid arthritis. , 2004, Bioorganic & medicinal chemistry letters.

[152]  Lawrence C Kuo,et al.  Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors. , 2004, Journal of medicinal chemistry.

[153]  Sahil Patel,et al.  Apo and Inhibitor Complex Structures of BACE (β-secretase) , 2004 .

[154]  Renxiao Wang,et al.  The PDBbind database: collection of binding affinities for protein-ligand complexes with known three-dimensional structures. , 2004, Journal of medicinal chemistry.

[155]  Ruhong Zhou,et al.  Hydrophobic Collapse in Multidomain Protein Folding , 2004, Science.

[156]  W Patrick Walters,et al.  A detailed comparison of current docking and scoring methods on systems of pharmaceutical relevance , 2004, Proteins.

[157]  S. Kadono,et al.  Crystal structure of human factor VIIa/tissue factor in complex with peptide mimetic inhibitor. , 2004, Biochemical and biophysical research communications.

[158]  M Katharine Holloway,et al.  Identification of a small molecule nonpeptide active site beta-secretase inhibitor that displays a nontraditional binding mode for aspartyl proteases. , 2004, Journal of medicinal chemistry.

[159]  Punit Marathe,et al.  N-(cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. , 2004, Journal of medicinal chemistry.

[160]  B. Ruggeri,et al.  Development of vascular endothelial growth factor receptor (VEGFR) kinase inhibitors as anti-angiogenic agents in cancer therapy. , 2004, Current medicinal chemistry.

[161]  W. F. Hoffman,et al.  Optimization of the indolyl quinolinone class of KDR (VEGFR-2) kinase inhibitors: effects of 5-amido- and 5-sulphonamido-indolyl groups on pharmacokinetics and hERG binding. , 2004, Bioorganic & medicinal chemistry letters.

[162]  Matthew P. Repasky,et al.  Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. , 2004, Journal of medicinal chemistry.

[163]  Estrogen receptor microarrays: subtype-selective ligand binding. , 2004, Journal of the American Chemical Society.

[164]  S. Kuromitsu,et al.  YM-231146, a novel orally bioavailable inhibitor of vascular endothelial growth factor receptor-2, is effective against paclitaxel resistant tumors. , 2005, Biological & pharmaceutical bulletin.

[165]  Youwei Yan,et al.  P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold. , 2005, Bioorganic & medicinal chemistry letters.

[166]  P. A. Harris,et al.  Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors. , 2005, Journal of medicinal chemistry.

[167]  C. Venkatachalam,et al.  LigScore: a novel scoring function for predicting binding affinities. , 2005, Journal of molecular graphics & modelling.

[168]  K. Luk,et al.  RO4383596, an orally active KDR, FGFR, and PDGFR inhibitor: synthesis and biological evaluation. , 2005, Bioorganic & medicinal chemistry.

[169]  B. Berne,et al.  Drying and hydrophobic collapse of paraffin plates. , 2005, The journal of physical chemistry. B.

[170]  Toshiyuki Shimizu,et al.  Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N'-{4-(4-quinolyloxy)phenyl}ureas. , 2005, Journal of medicinal chemistry.

[171]  S. Kadono,et al.  Structure of human factor VIIa/tissue factor in complex with a peptide-mimetic inhibitor: high selectivity against thrombin by introducing two charged groups in P2 and P4. , 2005, Acta crystallographica. Section F, Structural biology and crystallization communications.

[172]  Andreas Schwienhorst,et al.  Thrombin inhibitors identified by computer-assisted multiparameter design. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[173]  Xin Chen,et al.  Synthesis and identification of [1,3,5]triazine-pyridine biheteroaryl as a novel series of potent cyclin-dependent kinase inhibitors. , 2005, Journal of medicinal chemistry.

[174]  Yutaka Maeda,et al.  Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[175]  Victor Guallar,et al.  Importance of accurate charges in molecular docking: Quantum mechanical/molecular mechanical (QM/MM) approach , 2005, J. Comput. Chem..

[176]  Youwei Yan,et al.  9-hydroxyazafluorenes and their use in thrombin inhibitors. , 2005, Journal of medicinal chemistry.

[177]  Thierry Langer,et al.  Recent Advances in Docking and Scoring , 2005 .

[178]  Tsukasa Suzuki,et al.  Novel interactions of large P3 moiety and small P4 moiety in the binding of the peptide mimetic factor VIIa inhibitor. , 2005, Biochemical and biophysical research communications.

[179]  T. Kayahara,et al.  Optimization of a coagulation factor VIIa inhibitor found in factor Xa inhibitor library. , 2005, Bioorganic & medicinal chemistry.

[180]  Ruhong Zhou,et al.  Observation of a dewetting transition in the collapse of the melittin tetramer , 2005, Nature.

[181]  A. Kiselyov,et al.  Hetaryl imidazoles: a novel dual inhibitors of VEGF receptors I and II. , 2006, Bioorganic & medicinal chemistry letters.

[182]  J. Janc,et al.  Factor VIIa inhibitors: chemical optimization, preclinical pharmacokinetics, pharmacodynamics, and efficacy in an arterial baboon thrombosis model. , 2006, Bioorganic & medicinal chemistry letters.

[183]  R. Friesner,et al.  Novel procedure for modeling ligand/receptor induced fit effects. , 2006, Journal of medicinal chemistry.

[184]  A. Kiselyov,et al.  N-(Aryl)-4-(azolylethyl)thiazole-5-carboxamides: novel potent inhibitors of VEGF receptors I and II. , 2006, Bioorganic & medicinal chemistry letters.

[185]  A. Kiselyov,et al.  Inhibitors of VEGF receptors-1 and -2 based on the 2-((pyridin-4-yl)ethyl)pyridine template. , 2006, Bioorganic & medicinal chemistry letters.

[186]  H. Pershadsingh.  Dual Peroxisome Proliferator-Activated Receptor-α/γ Agonists , 2012 .

[187]  R. Friesner,et al.  New insights about HERG blockade obtained from protein modeling, potential energy mapping, and docking studies. , 2006, Bioorganic & medicinal chemistry.