Protein kinases are major therapeutic targets for a variety of diseases such as cancer, diabetes, and inflammation. In recent years, many small-molecule inhibitors of protein kinases have been developed as possible treatments of these diseases. However, binding specificity still remains a critical issue in the development of protein kinase inhibitors because of the high structural similarity between different kinases. In this work, we first investigated the binding specificity and binding mechanism of Gleevec and its analog G6G. An extensive molecular dynamics free energy study was carried out in order to compare the binding affinities of Gleevec and G6G to Abl and Src kinase domains, in which alchemical free energy perturbation replica-exchange molecular dynamics (FEP/REMD) and umbrella sampling (US) simulations with explicit solvent were performed. The dissection of the absolute binding free energy of Gleevec and G6G to the kinases provides new insight into the molecular and chemical determinants explaining why these kinases display very different specificity for Gleevec but achieve equal potency in binding G6G. Next, we focus our efforts on how to engineer binding selectivity. To achieve the desired selectivity profile, we are developing a protocol on refining a ligand and evaluating the refinement with free energy perturbation calculations. Kinase inhibitor lapatinib is selected as the model system in this study. Lapatinib displays a <i>K</i><sub>d</sub> value of 2.4, 54, and &gt; 10000 nM for EGFR, ERBB4, and Src respectively. We aim to achieve a selectivity profile such that the binding affinity to EGFR is maintained, while those to ERBB4 and Src can be swapped.

Improving kinase inhibitor selectivity with free energy perturbation molecular dynamics simulations

251st National Meeting (2016)

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