title: Elucidating substrate promiscuity in the human cytochrome 3A4.
abstract: The human cytochrome P450 enzymes (CYPs) are heme-protein monooxygenases, which catalyze oxidative reactions of a broad spectrum of substrates. Consequently, they play a critical role in the metabolism of xenobiotics, such as drugs and carcinogens, and the catabolism of endogenous lipophilic factors. Bioavailability and toxicity, both of which can be related to CYPs, continue to pose problems in the development of new drugs. The isoform which metabolizes over one-third of drugs, CYP 3A4, was investigated employing ensemble-docking experiments of a 195-substrate library with induced fit and GOLD docking algorithms and a number of scoring functions. Enzyme conformations included three currently available CYP 3A4 crystal structures. All docking experiments were performed in duplicates with and without inclusion of crystallographic waters. Resultant poses were assessed based on accuracy of site of metabolism prediction. Analyses of the docked solutions pertaining to ranking efficacy, ligand molecular properties, stabilizing residues in the ligand-enzyme complexes, and metabolic reactions are discussed. Our analyses suggest that certain residues make favorable interactions with the bound substrates. Employing multiple receptor conformations enhances the accuracy of catalytic prediction, while ligand size and flexibility impact docking performance. The presence of waters observed in crystal complexes does not necessarily lead to improved performance.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, Edwardsville, Illinois 62034, United States.
authors.forename: Christina
authors.initials: C
authors.lastname: Hayes
authors.forename: Daniel
authors.initials: D
authors.lastname: Ansbro
authors.forename: Maria
authors.initials: M
authors.lastname: Kontoyianni
mesh_terms: D001665:Binding Sites; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human