Heat shock protein 90 (Hsp90) is an ATP-dependent chaperone involved in the stabilization of several overexpressed oncogenic proteins. Thus, the ATPase activity of Hsp90 is an appealing target for cancer therapeutics. In the current work, we used alchemical absolute binding free energy calculations to evaluate the binding of several inhibitors to the ATP binding domain of Hsp90. The first part of this contribution aims to test different types of restraints while computing binding free energies. Then, we compared our computational predictions of several Hsp90 complexes to the experimental affinities. We also applied a docking strategy to predict binding sites of a set of Hsp90 inhibitors with no crystal structures. We discuss our results as well as insights gained. This investigation presents detailed structural information about Hsp90-ligand interactions with the goal of contributing to the design of novel and potent Hsp90 inhibitors.

Absolute binding free energy predictions for heat shock protein 90 (Hsp90) complexes

2019 Fall National Meeting

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