Integrated molecular docking and ADMET-based computational investigation of potent phytochemicals from multiple medicinal plants as CYP2E1 inhibitors

Cytochrome P450 2E1 (CYP2E1) is a heme-containing monooxygenase involved in xenobiotic metabolism and oxidative stress generation, making it a significant
therapeutic target. The present study aimed to identify potent natural inhibitors of CYP2E1 through an integrated molecular docking and ADMET-based computational approach. Twenty structurally diverse phytochemicals were selected
from medicinal plants based on reported pharmacological relevance. Molecular docking was performed to evaluate binding affinity and interaction stability within
the CYP2E1 active site. Docking results demonstrated that several compounds effectively occupied the catalytic pocket and interacted with key residues such as CYS437, ILE115, LEU368, ALA299, VAL364, and PHE430. Shatavarin IV
exhibited the highest binding affinity (–12.9 kcal/mol), surpassing the native ligand (–12 kcal/mol), followed by Amygdalin (–10.2 kcal/mol). Withaferin A, Curcumin,
Galangin, Aloe-emodin, and Ferulic acid also exhibited favorable hydrogenbonding and hydrophobic interaction profiles within the active site, suggesting
potential CYP2E1 inhibitory activity based on computational predictions. Comprehensive ADMET analysis revealed important pharmacokinetic differences among the candidates. Although Shatavarin IV displayed superior docking performance, its high molecular weight and polarity suggested limited oral
absorption. In contrast, Ferulic acid, Curcumin, Aloe-emodin, and Withaferin A
demonstrated balanced physicochemical properties, improved intestinal
absorption, acceptable metabolic profiles, and comparatively lower toxicity risks.
Overall, Ferulic acid emerged as the most promising candidate when both binding
efficiency and pharmacokinetic suitability were considered, warranting further
experimental validation. Future studies should focus on molecular dynamics
simulations and in vitro/in vivo validation to confirm stability, efficacy, and safety
profiles.