title: In silico description of differential enantioselectivity in methoxychlor O-demethylation by CYP2C enzymes.
abstract: Methoxychlor undergoes metabolism by cytochrome P450 (CYP) enzymes forming a chiral mono-phenolic derivative (Mono-OH-M) as main metabolite. In the current study, members of the CYP2C family were examined for their chiral preference in Mono-OH-M formation. CYP2C9 and CYP2C19 possessed high enantioselectivity favoring the formation of S-Mono-OH-M; CYP2C3 showed no enantioselectivity, whereas CYP2C5 slightly favored the formation of R-Mono-OH-M. Molecular modeling calculations were utilized in order to explain the observed differences in chiral preference of CYP2C enzymes. Molecular docking calculations could describe neither the existence of chiral preference in metabolism, nor the enantiomer which is preferentially formed. Molecular dynamic calculations were also carried out and were found to be useful for accurate description of chiral preference in biotransformation of methoxychlor by CYP2C enzymes. An in silico model capable of predicting chiral preference in cytochrome P450 enzymes in general can be developed based on the analysis of the stability and rigidity parameters of interacting partners during molecular dynamic simulation.
authors.affiliation: Virtua Drug, Ltd., H-1015 Budapest, Csalogány st. 4c, Hungary.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bikádi
authors.forename: Eszter
authors.initials: E
authors.lastname: Hazai
mesh_terms: D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D006418:Heme; D006801:Humans; D008731:Methoxychlor / Q000737:chemistry* / Q000378:metabolism*; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D004364:Pharmaceutical Preparations / Q000737:chemistry; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013237:Stereoisomerism; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D004364:Pharmaceutical Preparations; C400322:cytochrome P-450 CYP2C subfamily; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D008731:Methoxychlor