Tyrosine kinases are attractive drug targets for curing certain types of cancers. Gleevec, a well-known cancer therapeutic agent, is sufficient to inhibit several tyrosine kinases with good efficacy, including Abl and c-Kit kinases. But it shows less or weak potency to inhibit the homologous tyrosine kinases, such as Lck and c-Src kinases. Because the drug binding features in Abl and c-Kit kinase domains are highly conserved in Lck and c-Src, it is unclear the binding selectivity of Gleevec to the tyrosine kinases solely based on structural explanations. Molecular dynamics free energy perturbation simulations with restraining potentials as well as umbrella sampling calculations have been performed to compute the absolute binding free energies of Gleevec to Abl, c-Kit, Lck, and c-Src in explicit water solvent to elucidate the main factors dominating Gleevec's binding recognition and diverse specificity to the kinases. The calculated absolute binding free energies yield good agreement with the experiment. We found that the dispersive contribution is the dominant factor governing Gleevec binding to the kinases that compensates about two-third of the unfavorable energy penalty of losing the translational, rotational, and conformational freedom of the ligand upon binding. The effects of the electrostatic and repulsive contributions to the binding affinity are offset due to the cancelation of solvent effects. Additionally, our calculations reveal that Abl kinase provides the most exceptional electrostatic and attractive van der Waals protein-ligand interactions for stabilizing Gleevec in the binding pocket. Abl also loses the least penalty brought on the translational, rotational, and conformational flexibility of Gleevec upon binding. Furthermore, our calculations suggest the conformational significance of the activation loop for tyrosine kinase bound to Gleevec. Our findings provide physical bases to aid in structural-based drug design for inhibitors of the tyrosine kinases.

Binding and recognition of Gleevec by Src-family kinases

243rd National Meeting (2012)

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