Accurate prediction of binding affinities of drug candidates to their targets remains challenging because of protein flexibility. In case of CDK2 and ERK2 kinases, conformational flexibility of the glycine-rich loop in the drug-binding site was identified using MD simulations. The binding free energy (delta-G) of twenty-four ATP-competitive inhibitors toward these kinases was assessed using an alchemical free energy perturbation method, MP-CAFEE. However, large calculation errors of 2-3 kcal/mol were observed when using this method, where the free energy simulation starts from a single equilibrated conformation. Here, we have developed a new delta-G computation method, where the starting structure was set to multi-conformations to cover flexibility, showing significant improvement in prediction accuracy. The present study demonstrates that conformational flexibility of interactions between a compound and the glycinerich loop in the kinases is a key factor in delta-G estimation.<br/>The protein-drug binding free energy computation has been applied to prediction of mutation-induced drug sensitivity changes in oncogenic kinases. Recently, a RET mutation (S904F) has been reported to confer resistance to a tyrosine-kinase inhibitor, vandetanib, and interestingly this residue is located in the activation loop and away from the drug binding site (~26 angstroms). Microsecond MD simulations show that the mutation causes not only decreasing the flexibility of the activation loop but also a significant geometrical distortion of the hydrogen-bond network connecting this loop, alpha-C helix, and glycine-rich loop. Furthermore, delta-G computation based on these trajectories characterizes a mutant-specific transient conformer incompatible with binding of the drug, supporting experimentally-measured thermal instability of the RET mutant complexed with vandetanib. Combination of long-timescale MD simulations and our developed delta-G computation method suggests the significance of a mutation-triggered allosteric conformational change on drug resistance.

Protein-drug binding free energy computation incorporating protein flexibility and its significance in predicting mutation-induced drug resistance in oncogenic kinases

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.