title: Computational and in vitro studies on the inhibitory effects of herbal compounds on human cytochrome P450 1A2.
abstract: Human CYP1A2 is an important enzyme for drug metabolism and procarcinogen activation. This study aimed to explore the binding mode of ligands with CYP1A2 and to screen potential inhibitors from a library of herbal compounds using computational and in vitro approaches.        The heme prosthetic group and six residues (Thr124, Phe125, Phe226, Phe260, Gly316, and Ala317) in the active site of CYP1A2 were identified as important residues for ligand binding using the LIGPLOT program. Ala317 in helix I immediately above heme was highly conserved in most human CYPs with known crystal structures.        In molecular docking, 19 of the 56 herbal compounds examined were identified as potential inhibitors of CYP1A2. Up to 21 of the 56 herbal compounds were hit by the pharmacophore model of CYP1A2 inhibitors developed and validated in this study.        In the in vitro inhibition study, 8 herbal compounds were identified as moderate to potent inhibitors of CYP1A2. Five of the 8 herbal compounds predicted to be potential inhibitors were confirmed as CYP1A2 inhibitors in the in vitro study.        A combination of computational and in vitro approaches, represent a useful tool to identify potential inhibitors for CYP1A2 from herbal compounds.
authors.affiliation: School of Health Sciences & Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Yang
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Zhou
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Chen
authors.forename: Chun Guang
authors.initials: CG
authors.lastname: Li
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Sneed
authors.forename: Jun
authors.initials: J
authors.lastname: Liang
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D003198:Computer Simulation; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006418:Heme / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D028321:Plant Preparations / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D015203:Reproducibility of Results; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D000596:Amino Acids; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D028321:Plant Preparations; D006418:Heme; D019388:Cytochrome P-450 CYP1A2