Identification of Potential Dual HDAC6 and HSP90 Inhibitors for the Treatment of Cancer using Molecular Docking, Molecular Dynamics and MM/PBSA Studies: A Comprehensive In Silico Study.

Background: Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. The interaction of these proteins within the cytosolic complex plays a critical role in regulating cancer cell survival and progression. Notably, current studies highlight that the simultaneous inhibition of HDAC6 and Hsp90 can produce synergistic effects and offer a promising therapeutic potential for combating malignant cancers.

Objective: The objective of this study was to explore potential compounds that can inhibit both HDAC6 and Hsp90 proteins.

Methods: In this study, a number of in-silico computational techniques were employed. A total of 791 molecules, sharing at least 30% similarity with previously identified four HDAC inhibitors, were obtained from the ZINC15 database and subjected to docking on HDAC6 and Hsp90 proteins. The top eight ligands demonstrating the best binding scores against both targets, with panobinostat and ganetespib serving as reference compounds for HDAC6 and Hsp90, respectively, were selected for further analysis. Subsequently, ADME prediction and molecular dynamics simulations were conducted on the selected ligands.

Results: A detailed molecular docking, molecular dynamics simulations and ADME studies have revealed that ZINC27653366 exhibited the highest inhibitory potential against both Hsp90 and HDAC6 target proteins, making it the most promising inhibitor.

Conclusion: In conclusion, although additional in vitro and in vivo studies are required for the validation, in silico evaluation of ZINC27653366 may position it as a promising candidate for the treatment of different types of cancers.