Binary quantitative activity-activity relationship (QAAR) studies to explore selective HDAC8 inhibitors: In light of mathematical models, DFT-based calculation and molecular dynamic simulation studies

Abstract

Histone deacetylase 8 (HDAC8) selectivity over other HDACs is a major concern of interest, since HDAC8 has been implicated as a potential drug target of many diseases including haematological malignancy. Quantitative activity-activity relationship (QAAR) study is a good strategy to explore the possible features to design HDAC8 selective inhibitors. Here, a mathematical framework has been constructed to understand the important molecular fragments responsible for HDAC8 selectivity over HDAC1, 2 and 3. This study also deals with binary QAAR-based HDAC8 selectivity screening of some in-house molecules and understanding the toxicity of the in-house molecules using DFT-based descriptors. Further, this study explores the possible binding mechanism of in-house compounds with HDAC8 by molecular dynamic simulation. Hence, the comparative learning amongst the mathematical models, DFT-based calculation and molecular dynamic simulation methods will surely enrich the scientific community to design selective HDAC8 inhibitors in future.