Tyrosine kinases are crucial to cellular signaling that regulates cell growth, proliferation, metabolism, differentiation and migration. Therefore, they are attractive drug targets for curing certain types of cancers, such as chronic myeloid leukemia (CML). Gleevec, a well-known cancer therapeutic agent, is a potent inhibitor of Abl kinases, but it is not an effective inhibitor of the highly homologous c-Src kinase. A computational study of Gleevec binding to c-Abl and c-Src kinases is presented here, with the goal of explaining the difference in binding potency from a free energy point of view. The roles of conformational selection and binding to DFG-out conformation are explicitly explored. The �string method with swarms-of-trajectories� combined with umbrella sampling simulations have been used to compute the free energy difference between the active and the DFG-out inactive conformations In addition, alchemical free energy perturbation molecular dynamics (FEP/MD) simulations have been performed to compute the absolute binding free energies of Gleevec to c-Abl and c-Src in explicit water solvent to explore the main factors dominating Gleevec's binding recognition and diverse specificity to the kinases.

Why is Gleevec a specific and potent inhibitor of Abl but not of c-Src?

244th National Meeting (2012)

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