title: Explaining why Gleevec is a specific and potent inhibitor of Abl kinase.
abstract: Tyrosine kinases present attractive drug targets for specific types of cancers. Gleevec, a well-known therapeutic agent against chronic myelogenous leukemia, is an effective inhibitor of Abl tyrosine kinase. However, Gleevec fails to inhibit closely homologous tyrosine kinases, such as c-Src. Because many structural features of the binding site are conserved, the molecular determinants responsible for binding specificity are not immediately apparent. Some have attributed the difference in binding specificity of Gleevec to subtle variations in ligand-protein interactions (binding affinity control), whereas others have proposed that it is the conformation of the DFG motif, in which ligand binding is only accessible to Abl and not to c-Src (conformational selection control). To address this issue, the absolute binding free energy was computed using all-atom molecular dynamics simulations with explicit solvent. The results of the free energy simulations are in good agreement with experiments, thereby enabling a meaningful decomposition of the binding free energy to elucidate the factors controlling Gleevec's binding specificity. The latter is shown to be controlled by a conformational selection mechanism and also by differences in key van der Waals interactions responsible for the stabilization of Gleevec in the binding pocket of Abl.
authors: Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, The University of Chicago, Chicago, IL 60637, USA.
authors: Yen-Lin
authors: YL
authors: Lin
authors: Yilin
authors: Y
authors: Meng
authors: Wei
authors: W
authors: Jiang
authors: Benoît
authors: B
authors: Roux
mesh_terms: D001549:Benzamides; D001665:Binding Sites; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology; D008958:Models, Molecular; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl; D016392:Proto-Oncogene Proteins pp60(c-src)