Enhancing the Sensitivity of Pharmacophore-Based Virtual Screening by Incorporating Customized ZBG Features: A Case Study Using Histone Deacetylase 8

Abstract

As key regulators of epigenetic regulation, human histone deacetylases (HDACs) have been identified as drug targets for the treatment of several cancers. The proper recognition of zinc-binding groups (ZBGs) will help improve the accuracy of virtual screening for novel HDAC inhibitors. Here, we developed a high-specificity ZBG-based pharmacophore model for HDAC8 inhibitors by incorporating customized ZBG features. Subsequently, pharmacophore-based virtual screening led to the discovery of three novel HDAC8 inhibitors with low micromole IC₅₀ values (1.8–1.9 μM). Further studies demonstrated that compound <b>H8-A5</b> was selective for HDAC8 over HDAC 1/4 and showed antiproliferation activity in MDA-MB-231 cancer cells. Molecular docking and molecular dynamic studies suggested a possible binding mode for <b>H8-A5</b>, which provides a good starting point for the development of HDAC8 inhibitors in cancer treatment