KIDFamMap: a database of kinase-inhibitor-disease family maps for kinase inhibitor selectivity and binding mechanisms

Kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases. Designing selective kinase inhibitors is an emergent and challenging task, because kinases share an evolutionary conserved ATP-binding site. KIDFamMap (http://gemdock.life.nctu.edu.tw/KIDFamMap/) is the first database to explore kinase-inhibitor families (KIFs) and kinase-inhibitor-disease (KID) relationships for kinase inhibitor selectivity and mechanisms. This database includes 1208 KIFs, 962 KIDs, 55 603 kinase-inhibitor interactions (KIIs), 35 788 kinase inhibitors, 399 human protein kinases, 339 diseases and 638 disease allelic variants. Here, a KIF can be defined as follows: (i) the kinases in the KIF with significant sequence similarity, (ii) the inhibitors in the KIF with significant topology similarity and (iii) the KIIs in the KIF with significant interaction similarity. The KIIs within a KIF are often conserved on some consensus KIDFamMap anchors, which represent conserved interactions between the kinase subsites and consensus moieties of their inhibitors. Our experimental results reveal that the members of a KIF often possess similar inhibition profiles. The KIDFamMap anchors can reflect kinase conformations types, kinase functions and kinase inhibitor selectivity. We believe that KIDFamMap provides biological insights into kinase inhibitor selectivity and binding mechanisms.

[1]  G. Hong,et al.  Nucleic Acids Research , 2015, Nucleic Acids Research.

[2]  Susan O'Brien,et al.  Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  Theonie Anastassiadis,et al.  Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity , 2011, Nature biotechnology.

[4]  Michele Magrane,et al.  UniProt Knowledgebase: a hub of integrated protein data , 2011, Database J. Biol. Databases Curation.

[5]  Mindy I. Davis,et al.  A quantitative analysis of kinase inhibitor selectivity , 2008, Nature Biotechnology.

[6]  Susumu Goto,et al.  KEGG for integration and interpretation of large-scale molecular data sets , 2011, Nucleic Acids Res..

[7]  Frances M. G. Pearl,et al.  MoKCa database—mutations of kinases in cancer , 2008, Nucleic Acids Res..

[8]  M. Kimmel,et al.  Conflict of interest statement. None declared. , 2010 .

[9]  Norbert Haider,et al.  Functionality Pattern Matching as an Efficient Complementary Structure/Reaction Search Tool: an Open-Source Approach , 2010, Molecules.

[10]  S. Hubbard.  Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog , 1997, The EMBO journal.

[11]  Richard A Norman,et al.  Structural approaches to obtain kinase selectivity. , 2012, Trends in pharmacological sciences.

[12]  Chih-Chieh Chen,et al.  (PS)2: protein structure prediction server , 2006, Nucleic Acids Res..

[13]  K. Shokat,et al.  The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. , 2011, Annual review of biochemistry.

[14]  E. Canaani,et al.  Chronic myelogenous leukemia: biology and therapy. , 1993, Leukemia.

[15]  Chih-Chieh Chen,et al.  (PS)2-v2: template-based protein structure prediction server , 2009, BMC Bioinformatics.

[16]  John P. Overington,et al.  ChEMBL: a large-scale bioactivity database for drug discovery , 2011, Nucleic Acids Res..

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

[18]  Alan F. Scott,et al.  McKusick's Online Mendelian Inheritance in Man (OMIM®) , 2008, Nucleic Acids Res..

[19]  Xin Wen,et al.  BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities , 2006, Nucleic Acids Res..

[20]  References , 1971 .

[21]  P E Bourne,et al.  Protein structure alignment by incremental combinatorial extension (CE) of the optimal path. , 1998, Protein engineering.

[22]  E. Birney,et al.  Pfam: the protein families database , 2013, Nucleic Acids Res..

[23]  Hilmar Weinmann Dr. and,et al.  Editorial: Drug Discovery Process for Kinease Inhibitors , 2005 .

[24]  P Reichardt,et al.  Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  Paul Reichert,et al.  Crystal structures of MEK1 binary and ternary complexes with nucleotides and inhibitors. , 2009, Biochemistry.

[26]  Wei-Sheng Huang,et al.  Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. , 2010, Journal of medicinal chemistry.

[27]  N. Guex,et al.  SWISS‐MODEL and the Swiss‐Pdb Viewer: An environment for comparative protein modeling , 1997, Electrophoresis.

[28]  J. Radich,et al.  Measuring response to BCR‐ABL inhibitors in chronic myeloid leukemia , 2012, Cancer.

[29]  David S. Goodsell,et al.  The RCSB Protein Data Bank: redesigned web site and web services , 2010, Nucleic Acids Res..

[30]  Kai-Cheng Hsu,et al.  SiMMap: a web server for inferring site-moiety map to recognize interaction preferences between protein pockets and compound moieties , 2010, Nucleic Acids Res..

[31]  Tim J. P. Hubbard,et al.  SCOP database in 2004: refinements integrate structure and sequence family data , 2004, Nucleic Acids Res..

[32]  Hilmar Weinmann,et al.  Drug discovery process for kinase inhibitors. , 2005, Chembiochem : a European journal of chemical biology.

[33]  Robert D. Finn,et al.  InterPro: the integrative protein signature database , 2008, Nucleic Acids Res..

[34]  Richard Wooster,et al.  BRAF and RAS mutations in human lung cancer and melanoma. , 2002, Cancer research.

[35]  Angel Herráez,et al.  Biomolecules in the computer: Jmol to the rescue , 2006, Biochemistry and molecular biology education : a bimonthly publication of the International Union of Biochemistry and Molecular Biology.

[36]  Chun-Yu Lin,et al.  PPISearch: a web server for searching homologous protein–protein interactions across multiple species , 2009, Nucleic Acids Res..

[37]  J. Kuriyan,et al.  The Conformational Plasticity of Protein Kinases , 2002, Cell.

[38]  Evan Bolton,et al.  PubChem's BioAssay Database , 2011, Nucleic Acids Res..

[39]  Jonathan D Cooper,et al.  p38α stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis , 2004, Molecular and Cellular Neuroscience.

[40]  R. Venkataraghavan,et al.  Atom pairs as molecular features in structure-activity studies: definition and applications , 1985, J. Chem. Inf. Comput. Sci..

[41]  N. Gray,et al.  Targeting cancer with small molecule kinase inhibitors , 2009, Nature Reviews Cancer.

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

[43]  S. Clifton,et al.  Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation. , 1995, Genomics.

[44]  Mindy I. Davis,et al.  Comprehensive analysis of kinase inhibitor selectivity , 2011, Nature Biotechnology.

[45]  Kai-Cheng Hsu,et al.  Core Site-Moiety Maps Reveal Inhibitors and Binding Mechanisms of Orthologous Proteins by Screening Compound Libraries , 2012, PloS one.

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

[47]  L. Tong,et al.  Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site , 2002, Nature Structural Biology.

[48]  L. Johnson,et al.  Protein Kinase Inhibitors: Insights into Drug Design from Structure , 2004, Science.

[49]  Hilmar Weinmann,et al.  Editorial: Drug Discovery Process for Kinease Inhibitors , 2005 .

[50]  Jeffrey Jie-Lou Liao,et al.  Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. , 2007, Journal of medicinal chemistry.

[51]  John M. Barnard,et al.  Chemical Similarity Searching , 1998, J. Chem. Inf. Comput. Sci..

[52]  Thomas Lengauer,et al.  Evaluation of the FLEXX incremental construction algorithm for protein–ligand docking , 1999, Proteins.

[53]  Malcolm J. McGregor,et al.  A Pharmacophore Map of Small Molecule Protein Kinase Inhibitors , 2007, J. Chem. Inf. Model..

[54]  James D. Griffin,et al.  Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants. , 2010, Blood.

[55]  T. Hunter,et al.  The Protein Kinase Complement of the Human Genome , 2002, Science.

[56]  P. Cohen.  Protein kinases — the major drug targets of the twenty-first century? , 2002, Nature reviews. Drug discovery.

[57]  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..

[58]  Jinn-Moon Yang,et al.  GEMDOCK: A generic evolutionary method for molecular docking , 2004, Proteins.

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