Structural And Energetic Insight Into The Interactions Between The Benzolactam Inhibitors And Tumor Marker Hsp90 Alpha

The heat shock protein 90 alpha (HSP90 alpha) provides a promising molecular target for cancer therapy. A series of novel benzolactam inhibitors exhibited distinct inhibitory activity for HSP90 alpha. However, the structural basis for the impact of distinct R-1 substituent groups of nine benzolactam inhibitors on HSP90 alpha binding affinities remains unknown. In this study, we carried out molecular docking, molecular dynamics (MD) simulations, and molecular mechanics and generalized Born/surface area (MM-GBSA) binding free energy calculations to address the differences. Molecular docking studies indicated that all nine compounds presented one conformation in the ATP-binding site of HSP90 alpha N-terminal domain. MD simulations and subsequent MM-GBSA calculations revealed that the hydrophobic interactions between all compounds and HSP90 alpha contributed the most to the binding affinity and a good linear correlation was obtained between the calculated and the experimental binding free energies (R = 0.88). The per residue decomposition revealed that the most remarkable differences of residue contributions were found in the residues Ala55, Ile96, and Leu107 defining a hydrophobic pocket for the R-1 group, consistent with the analysis of binding modes. This study may be helpful for the future design of novel HSP90 alpha inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.