In silico metabolite profiling and molecular simulation of scopoletin derivatives as CYP3A4 modulators: a pharmacometabolomic strategy against aflatoxin B 1 bioactivation

Aflatoxin B₁ (AFB₁) is a potent hepatocarcinogen. It is activated by cytochrome P450 3A4 (CYP3A4) into a DNA-reactive epoxide linked to liver cancer.Six scopoletin metabolites were predicted using SmartCYP. Their lipophilicity was assessed via BioTransformer 3.0; molecular docking was performed with CBDock 2 using CYP3A4 (PDB ID: 1TQN).Phase I Metabolite 2 showed the highest binding affinity (Vina score: -7.4 kcal/mol) and was selected for a 100 ns molecular dynamics (MD) simulation using Desmond with the OPLS3e force field.The metabolite maintained stable binding (RMSD < 1.0 Å), showed >80% hydrophobic interaction occupancy with Phe215, Phe108, and Leu210, and formed transient hydrogen bonds with Ser119; MM-GBSA predicted a binding free energy of -75 kcal/mol.Scopoletin metabolites may competitively inhibit AFB₁ activation by binding CYP3A4, indicating potential for chemoprevention pending experimental confirmation.