Computational Evaluation of Prenylated Pterocarpans as Putative BRD4 Ligands: DFT, Antioxidant Thermochemistry, ADMET, Docking, and Molecular Dynamics

ABSTRACT

Prenylated pterocarpans and their derivatives (1‐6, 1a‐3a) were investigated using DFT calculations, antioxidant thermochemistry, pharmacokinetic and toxicity predictions, molecular docking, 150 ns molecular dynamics (MD) simulations, and MM/GBSA analyses to assess their electronic properties and potential as putative BRD4 ligands. DFT calculations revealed highest occupied molecular orbital (HOMO) localization mainly on aromatic and prenyl groups and lowest unoccupied molecular orbital (LUMO) localization on oxygenated regions, with compounds 2a, 3a, and 6 showing higher predicted electronic reactivity. SwissADME and ProTox‐III analyses indicated favorable drug‐likeness, oral bioavailability, and acceptable predicted toxicity profiles. PASS Online predicted potential anticancer, antioxidant, anti‐inflammatory, and antibacterial activities, particularly for compounds 4–6. Molecular docking showed favorable predicted binding affinities toward BRD4 (‐8.1 to ‐9.3 kcal mol ⁻¹ ), involving key residues such as Asn140, Trp81, and Tyr97. The 150 ns MD simulations, assessed through RMSD, RMSF, radius of gyration, SASA, and hydrogen‐bond analyses, supported the structural stability of the BRD4‐ligand complexes and revealed ligand‐dependent differences in flexibility, compactness, solvent exposure, and hydrogen‐bond persistence. MM/GBSA analysis identified compounds 3a, 2a, and 1a as the most promising predicted binders. Overall, these findings highlight prenylated pterocarpans as promising scaffolds for further investigation as potential BRD4 ligands, although experimental studies are required to validate their binding and inhibitory activities.