Tyrosine kinases present attractive drug targets for specific types of cancers. Gleevec, a well-known cancer therapeutic agent, is an effective inhibitor of several tyrosine kinases, including Abl and c-Kit kinases. But it shows less or weak potency to inhibit closely homologous tyrosine kinases, such as Lck and c-Src kinases. Because many structural features of the binding site are highly conserved in Abl and c-Kit as well as in Lck and c-Src, the molecular determinants responsible for Gleevec's binding specificity are poorly understood. To address this issue, free energy perturbation molecular dynamics (FEP/MD) simulations with explicit solvent was applied to compute the binding affinity of Gleevec to Abl, c-Kit, Lck, and c-Src to obtain the quantitative contributions of individual thermodynamic effects controlling the binding specificity of Gleevec to the kinases. The results of the calculations are in good agreement with experiments, enabling a detailed decomposition of the binding free energy. The van der Waals dispersive interaction makes a dominant contribution, compensating about two-third of the unfavorable free energy penalty associated with the loss of translational, rotational, and conformational freedom of the ligand upon binding. The electrostatic and repulsive contributions to the binding affinity nearly cancel out due to solvent effects. The FEP/MD calculations reveal key features of Abl kinase underlying Gleevec binding. While Abl provides optimal electrostatic and attractive van der Waals protein-ligand interactions for stabilizing Gleevec in the binding pocket, it also yields the smallest free energy penalty associated with the loss of translational, rotational, and conformational flexibility upon ligand binding. Furthermore, the calculations point to the importance of the conformation of the activation loop. The computations provide a strong physical basis to suggest structural-based drug design for inhibitors of the tyrosine kinases.

Recognition of Gleevec by Src-family kinases

245th National Meeting (2013)

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