Knowledge based prediction of ligand binding modes and rational inhibitor design for kinase drug discovery.

toward kinase inhibitor discovery, with the result that several kinase inhibitors have been approved as drugs since 2001. The commercial success of imatinib (N-(4-methyl-3-(4-(pyridin-3yl)pyrimidin-2-ylamino)phenyl)-4-((4-methylpiperazin-1-l)methyl)benzamide) has provided a clear incentive for the continued pursuit of kinase inhibitor design.

[1]  Arup K. Ghose,et al.  Adapting Structure-Based Drug Design in the Paradigm of Combinatorial Chemistry and High-Throughput Screening: An Overview and New Examples with Important Caveats for Newcomers to Combinatorial Library Design Using Pharmacophore Models or Multiple Copy Simultaneous Search Fragments , 1999 .

[2]  Structural Aspects of Kinases and Their Inhibitors , 2005 .

[3]  D. Fairlie,et al.  A new paradigm for protein kinase inhibition: blocking phosphorylation without directly targeting ATP binding. , 2007, Drug discovery today.

[4]  S. Knapp,et al.  Crystal Structures of the p21-Activated Kinases PAK4, PAK5, and PAK6 Reveal Catalytic Domain Plasticity of Active Group II PAKs , 2007, Structure.

[5]  Pascal Furet,et al.  Structure-based design and protein X-ray analysis of a protein kinase inhibitor. , 2002, Bioorganic & medicinal chemistry letters.

[6]  R. Walter,et al.  The development of novel C-2, C-8, and N-9 trisubstituted purines as inhibitors of TNF-alpha production. , 2006, Bioorganic & medicinal chemistry letters.

[7]  Julien Michel,et al.  Protein-ligand binding affinity predictions by implicit solvent simulations: a tool for lead optimization? , 2006, Journal of medicinal chemistry.

[8]  Stephen Green,et al.  Cyclin-dependent kinase 4 inhibitors as a treatment for cancer. Part 1: identification and optimisation of substituted 4,6-bis anilino pyrimidines. , 2003, Bioorganic & medicinal chemistry letters.

[9]  Andrew Potter,et al.  Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity. , 2005, Journal of medicinal chemistry.

[10]  D. Borhani,et al.  Discovery of A-770041, a src-family selective orally active lck inhibitor that prevents organ allograft rejection. , 2006, Bioorganic & medicinal chemistry letters.

[11]  Stefan Bonn,et al.  Structural Analysis of Protein Kinase A Mutants with Rho-kinase Inhibitor Specificity* , 2006, Journal of Biological Chemistry.

[12]  G L Trainor,et al.  Quinazolines as cyclin dependent kinase inhibitors. , 2001, Bioorganic & medicinal chemistry letters.

[13]  L. Johnson,et al.  Effects of Phosphorylation of Threonine 160 on Cyclin-dependent Kinase 2 Structure and Activity* , 1999, The Journal of Biological Chemistry.

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

[15]  U. Ryde,et al.  Ligand affinities predicted with the MM/PBSA method: dependence on the simulation method and the force field. , 2006, Journal of medicinal chemistry.

[16]  C. Sawyers,et al.  Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[17]  N. P. Todorov,et al.  Receptor flexibility in de novo ligand design and docking. , 2005, Journal of medicinal chemistry.

[18]  Malcolm J. McGregor.  A Pharmacophore Map of Small Molecule Protein Kinase Inhibitors. , 2008 .

[19]  P. Bamborough,et al.  5-(1H-Benzimidazol-1-yl)-3-alkoxy-2-thiophenecarbonitriles as potent, selective, inhibitors of IKK-ε kinase , 2006 .

[20]  Julien Michel,et al.  Efficient Generalized Born Models for Monte Carlo Simulations. , 2006, Journal of chemical theory and computation.

[21]  B. Kuhn,et al.  Validation and use of the MM-PBSA approach for drug discovery. , 2005, Journal of medicinal chemistry.

[22]  P. Bamborough,et al.  5-(1H-Benzimidazol-1-yl)-3-alkoxy-2-thiophenecarbonitriles as potent, selective, inhibitors of IKK-epsilon kinase. , 2006, Bioorganic & Medicinal Chemistry Letters.

[23]  Oliver Hantschel,et al.  Regulation of the c-Abl and Bcr–Abl tyrosine kinases , 2004, Nature Reviews Molecular Cell Biology.

[24]  N. Gray,et al.  Rational design of inhibitors that bind to inactive kinase conformations , 2006, Nature chemical biology.

[25]  Christopher W Murray,et al.  Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation. , 2005, Journal of medicinal chemistry.

[26]  S. Knapp,et al.  Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. , 2003, Journal of molecular biology.

[27]  E. Perola.  Minimizing false positives in kinase virtual screens , 2006, Proteins.

[28]  Anna Vulpetti,et al.  An analysis of the binding modes of ATP-competitive CDK2 inhibitors as revealed by X-ray structures of protein-inhibitor complexes. , 2005, Current medicinal chemistry. Anti-cancer agents.

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

[30]  E. Goldsmith,et al.  Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine. , 2006, Acta biochimica et biophysica Sinica.

[31]  L. Johnson,et al.  Probing the ATP ribose-binding domain of cyclin-dependent kinases 1 and 2 with O(6)-substituted guanine derivatives. , 2002, Journal of medicinal chemistry.

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

[33]  A. Leach,et al.  Prediction of Protein—Ligand Interactions. Docking and Scoring: Successes and Gaps , 2006 .

[34]  C. E. Peishoff,et al.  A critical assessment of docking programs and scoring functions. , 2006, Journal of medicinal chemistry.

[35]  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.

[36]  Yoshihisa Suzuki,et al.  Crystal structures of proto-oncogene kinase Pim1: a target of aberrant somatic hypermutations in diffuse large cell lymphoma. , 2005, Journal of molecular biology.

[37]  Jeffrey Jie-Lou Liao,et al.  Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors , 2007 .

[38]  G. Bemis,et al.  BREED: Generating novel inhibitors through hybridization of known ligands. Application to CDK2, p38, and HIV protease. , 2004, Journal of medicinal chemistry.

[39]  Nicolas Foloppe,et al.  Identification of a buried pocket for potent and selective inhibition of Chk1: prediction and verification. , 2005, Bioorganic & medicinal chemistry.

[40]  D. Fabbro,et al.  The crystal structure of a c-Src complex in an active conformation suggests possible steps in c-Src activation. , 2005, Structure.

[41]  W. L. Jorgensen,et al.  General model for estimation of the inhibition of protein kinases using Monte Carlo simulations. , 2004, Journal of medicinal chemistry.

[42]  Osman F. Güner,et al.  Pharmacophore perception, development, and use in drug design , 2000 .

[43]  Peter M Fischer,et al.  Differential binding of inhibitors to active and inactive CDK2 provides insights for drug design. , 2006, Chemistry & biology.

[44]  G. Müller,et al.  Second-generation kinase inhibitors , 2005, Expert opinion on therapeutic targets.

[45]  Harald Schwalbe,et al.  NMR characterization of kinase p38 dynamics in free and ligand-bound forms. , 2006, Angewandte Chemie.

[46]  Paul D Lyne,et al.  Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. , 2006, Journal of medicinal chemistry.

[47]  R. Cramer,et al.  Topomer CoMFA: a design methodology for rapid lead optimization. , 2003, Journal of medicinal chemistry.

[48]  Krystal J Alligood,et al.  A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib) , 2004, Cancer Research.

[49]  T Honma,et al.  Crystallographic Approach to Identification of Cyclin-dependent Kinase 4 (CDK4)-specific Inhibitors by Using CDK4 Mimic CDK2 Protein* , 2001, The Journal of Biological Chemistry.

[50]  J. Murray,et al.  Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: protein structure-guided design and SAR. , 2006, Bioorganic & medicinal chemistry letters.

[51]  P. Furet,et al.  Strategies toward the design of novel and selective protein tyrosine kinase inhibitors. , 1999, Pharmacology & therapeutics.

[52]  R. Abagyan,et al.  Representing receptor flexibility in ligand docking through relevant normal modes. , 2005, Journal of the American Chemical Society.

[53]  D. Zaller,et al.  Structural basis for p38alpha MAP kinase quinazolinone and pyridol-pyrimidine inhibitor specificity. , 2003 .

[54]  Yixiang Cao,et al.  A Polarizable Force Field and Continuum Solvation Methodology for Modeling of Protein-Ligand Interactions. , 2005, Journal of chemical theory and computation.

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

[56]  L Meijer,et al.  Inhibition of cyclin-dependent kinases, GSK-3beta and CK1 by hymenialdisine, a marine sponge constituent. , 2000, Chemistry & biology.

[57]  Heather A Carlson,et al.  Exploring experimental sources of multiple protein conformations in structure-based drug design. , 2007, Journal of the American Chemical Society.

[58]  John Kuriyan,et al.  Crystal structure of the Src family tyrosine kinase Hck , 1997, Nature.

[59]  Hans Briem,et al.  From the Insoluble Dye Indirubin towards Highly Active, Soluble CDK2‐Inhibitors , 2005, Chembiochem : a European journal of chemical biology.

[60]  G M Crippen,et al.  Analysis of the in vitro antiviral activity of certain ribonucleosides against parainfluenza virus using a novel computer aided receptor modeling procedure. , 1989, Journal of medicinal chemistry.

[61]  Doriano Fabbro,et al.  Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia , 2006, Acta crystallographica. Section D, Biological crystallography.

[62]  David S. Nirschl,et al.  Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase. , 2008, Bioorganic & medicinal chemistry letters.

[63]  A. Ghose,et al.  Knowledge-based chemoinformatic approaches to drug discovery. , 2006, Drug discovery today.

[64]  T. Hunter,et al.  Oncogenic kinase signalling , 2001, Nature.

[65]  Oliver Hantschel,et al.  Organization of the SH3-SH2 unit in active and inactive forms of the c-Abl tyrosine kinase. , 2006, Molecular cell.

[66]  Arup K. Ghose,et al.  Combinatorial Library Design and Evaluation: Principles, Software, Tools, and Applications in Drug Discovery , 2001 .

[67]  A. Ghose,et al.  Determination of Pharmacophoric Geometry for Collagenase Inhibitors Using a Novel Computational Method and Its Verification Using Molecular Dynamics, NMR, and X-ray Crystallography , 1995 .

[68]  Matthew P. Repasky,et al.  Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. , 2006, Journal of medicinal chemistry.

[69]  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.

[70]  K. Shokat,et al.  Mutant tyrosine kinases with unnatural nucleotide specificity retain the structure and phospho-acceptor specificity of the wild-type enzyme. , 2002, Chemistry & biology.

[71]  S. A. Watkins,et al.  The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-a]pyridines. , 2004, Molecular cancer therapeutics.

[72]  M. Noble,et al.  Dissecting the determinants of cyclin-dependent kinase 2 and cyclin-dependent kinase 4 inhibitor selectivity. , 2006, Journal of medicinal chemistry.

[73]  Heather A Carlson,et al.  Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models. , 2007, Journal of the American Chemical Society.

[74]  M. Fleming,et al.  The Structure of Dimeric ROCK I Reveals the Mechanism for Ligand Selectivity* , 2006, Journal of Biological Chemistry.