title: Predicting oxidation sites with order of occurrence among multiple sites for CYP4A-mediated reactions.
abstract: To predict CYP4A-mediated reactions, we developed a two-dimensional template scoring system based on published data. The system predicts the order of occurrence among multiple oxidation sites, as well as the regioselectivity. The template has a linearly arranged honeycomb shape and an adjacent area. Molecules are overlaid on the template with the locations of the atoms restricted to the corners of hexagonal blocks. The overlaid conformers are then checked to determine whether they reside within the template area, and their position occupancy and position function scores are calculated. The position occupancy score is determined based on occupation of the respective positions on the template. The functional and steric properties are reflected in the position function score. The sum of these scores is compared among possible conformers, and the conformer with the highest total score is predicted to be preferentially metabolized. In the present study, prediction of sites of CYP4A-mediated oxidation and classification into substrates and non-substrates were performed for collected compounds, and agreement between predicted and experimental data exceeded 95% for substrates and non-substrates. The template scoring system can be easily linked to databases of two-dimensional chemical structures, and thus this system may be useful for drug development and studies of drug metabolism.
authors.affiliation: Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaura
authors.forename: Kouichi
authors.initials: K
authors.lastname: Yoshinari
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yamazoe
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D003879:Dermatologic Agents / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism*; D015474:Isotretinoin / Q000737:chemistry / Q000378:metabolism; D007850:Lauric Acids / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D009251:NADPH-Ferrihemoprotein Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D012984:Software; D013379:Substrate Specificity
chemical_list: D003879:Dermatologic Agents; D007527:Isoenzymes; D007850:Lauric Acids; D008024:Ligands; C030358:lauric acid; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D009251:NADPH-Ferrihemoprotein Reductase; D015474:Isotretinoin