Structure-based discovery of coumarin-derived HDAC2 inhibitor through integrated computational bioassays, steered molecular dynamics, network analysis and SAR

Histone deacetylase 2 (HDAC2) is a promising epigenetic target for cancer therapy; however, the clinical utility of Vorinostat (SAHA) is limited by poor selectivity, toxicity, and inadequate blood–brain barrier (BBB) permeability. A structure–activity relationship (SAR)-guided strategy was employed to identify novel coumarin-based HDAC2 inhibitors. A total of 2555 PubChem coumarin derivatives were filtered using Lipinski's criteria, yielding 1879 drug-like molecules for docking against HDAC2 (PDB ID: 7ZZT). Seventeen lead compounds guided the design of 46 novel derivatives. Docking identified compounds with binding affinities of −7.0 to −9.3 kcal/mol, exceeding SAHA (−7.3 kcal/mol). SAR analysis highlighted the coumarin scaffold, an additional aromatic ring, a 3–6 atom linker, a furan bridge, and terminal hydroxyl or methoxy groups as key structural features. Compound C5 exhibited high functional similarity with SAHA (R 2 = 0.898), favorable BBB permeability, superior predicted HDAC2 inhibition (IC 50 = 0.560 µM vs. 1.116 µM), enhanced predicted antiproliferative activity against MCF7, MDA-MB-231, HL-60, and U87MG cell lines, and stable binding confirmed by steered and 100 ns molecular dynamics simulations, identifying Asp104 as a key stabilizing residue.