Comprehensive Structure-Activity Relationship Analysis of Benzamide Derivatives as Histone Deacetylase 1 (HDAC1) Inhibitors.

A three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis incorporating ligand-receptor docking alignment and molecular dynamic (MD) simulations was conducted to elucidate the potent inhibitory effects of a series of benzamide derivatives on histone deacetylase 1 (HDAC1). A comparison between ligand-based (LB) and receptor-based (RB) 3D-QSAR models using molecular docking alignment produced statistically significant results. Steric and electrostatic contour maps provided insights into the interactions surrounding the benzamide ring, revealing that an increase in electron density enhances inhibitory activity. Furthermore, MD simulations were employed to investigate protein-ligand interactions in greater detail, yielding outcomes consistent with those from 3D-QSAR and molecular docking studies. This integrated approach of molecular docking, 3D-QSAR, and energy decomposition analysis derived from MD simulations, provides a valuable framework for the rational design of more potent HDAC1 inhibitors, facilitating the synthesis of highly effective anti-tumor compounds based on benzamide scaffolds.