title: Tyrosine kinase inhibition: Ligand binding and conformational change in c-Kit and c-Abl.
abstract: The conformational flexibility exhibited by protein kinases poses an enormous challenge to the design of cancer therapeutics. Additionally the high degree of structural conservation within the kinase superfamily often leads to inhibitors that exhibit little selectivity and substantial cross reactivity. This work investigates the conformational changes that accompany the binding of Gleevec, or imatinib mesylate, to the tyrosine kinases c-Kit and c-Abl. Our analysis is that this fit is driven, at least in part, by the need to exclude water from solvent-exposed backbone hydrogen bonds. Both experimental and molecular modeling studies of the active state inhibitor of the tyrosine kinase c-Abl indicate that solvent exclusion also plays a role in this system.
authors: Department of Chemistry, St. Edward's University, Austin, TX 78704, USA. healy@stedwards.edu
authors: Eamonn F
authors: EF
authors: Healy
authors: Skylar
authors: S
authors: Johnson
authors: Charles R
authors: CR
authors: Hauser
authors: Peter J
authors: PJ
authors: King
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides; D004611:Ellipticines / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D006860:Hydrogen Bonding; D000068877:Imatinib Mesylate; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D016415:Sequence Alignment; D014867:Water / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004611:Ellipticines; D008024:Ligands; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014867:Water; D000068877:Imatinib Mesylate; C008009:9-hydroxyellipticine; C496353:FGFR2 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051497:Receptor, Fibroblast Growth Factor, Type 2; D016315:Proto-Oncogene Proteins c-abl