Virtual Screening And Experimental Validation Of Novelhistone Deacetylase Inhibitors

Histone deacetylases(HDACs) are promising therapeutic targets for the treatment of tumor. Histone deacetylase inhibitors(HDACIs) not only have good effect in cancer treatment, but also demonstrate great therapeutic potential in diabetes and neurodegenerative diseases such as alzheimer’s disease. Three HDACIs, vorinostat(SAHA), romidepsin(FK228) and belinostat have been approved by the U.S. Food and Drug Administration(FDA) for the treatment of cutaneous and peripheral T cell lymphoma and some others are in the preclinical stage. HDACIs have provoked much interest amongst pharmacologists, scientific researchers and pharmaceutical companies as a new class of therapeutic agents. Discovery of novel HDACI lead compounds has vital significance for the drug research and development of HDACIs. In this study, we present a hierarchical virtual screening protocol for the identification of potential HDAC lead compounds. The protocol involves three main steps: 3D pharmacophorebased virtual screening, three-dimensional quantitative structure-activity relationship(3D-QSAR)-based virtual screening and molecular docking-based virtual screening. The pharmacophore modelling module GALAHAD and 3D-QSAR module CoMSIA in Computer aided drug design(CADD) software SYBYL-X2.0 and molecular docking software GOLD5.2 from Cambridge Crystallographic Data Center, UK are utilized for the implementation of three parts of the protocol, respectively. The virtual screening protocol was used for the screening of enamine database(www.enamine.net). The 22 final hit compounds were purchased and tested in vitro assay. Enzyme inhibition assays show that 3 out of 22 compounds have HDAC inhibitory activities. This study provide an effective virtual screening workflow of HDACIs. It has significant application value for the screening of HDACIs with novel scaffolds, highly activity and HDAC subtype selectivity.