Computational Investigation of Indazole fused Diarylurea scaffolds as Histone Deacetylase Inhibitor using Molecular Docking

Abstract

This study computationally evaluates eight novel indazole-fused diarylurea derivatives (C1–C8) as histone deacetylase (HDAC) inhibitors using molecular docking, MM-GBSA rescoring, molecular dynamics (MD), and ADMET profiling. Designed with systematic substitutions (H, F, CF₃) at the indazole and phenyl rings, the compounds were docked against HDAC1, HDAC2, HDAC3, and HDAC6. AutoDock Vina revealed C7 as the strongest binder (–10.1 kcal/mol) via π–π stacking and hydrophobic interactions, despite lacking Zn²⁺ coordination. C4 and C5 exhibited robust binding (–8.5 to –8.8 kcal/mol) through Zn²⁺ chelation, 4 H-bonds, and aromatic interactions, outperforming Sorafenib (–9.2 kcal/mol), which showed weak, non-specific contacts. MM-GBSA rescoring validated C4 (–10.8 kcal/mol) and C5 (–10.5 kcal/mol) as top candidates, surpassing vorinostat (–9.2 kcal/mol) in HDAC6 affinity. MD simulations confirmed C4’s stability in the HDAC6 pocket (RMSD ~1.5 Å) with persistent Zn²⁺ coordination and H-bond occupancy (>90%), outperforming vorinostat’s flexibility. Structure–activity relationships (SAR) highlighted electron-withdrawing groups (CF₃, F) as critical for affinity, while bulky substituents (OEt, OMe) reduced potency. ADMET predictions prioritized C4 and C8 (clogP ≈3.0–3.2, TPSA ≈100 Ų) for favorable drug-likeness, high GI absorption, and minimal toxicity (no hepatotoxicity/hERG risk), contrasting Sorafenib’s hepatotoxicity and CYP inhibition. Despite C7’s high docking score, its ethoxy group raised ADMET concerns. C4 and C8 emerged as optimal leads, combining Zn²⁺-mediated binding, multi-modal interactions (H-bonds, π–π stacking), and pharmacokinetic safety. This work underscores the potential of indazole-diarylurea scaffolds as selective HDAC inhibitors, with C4 and C8 warranting experimental validation for epigenetic cancer therapy.