Prediction of regioselectivity and preferred order of metabolisms on CYP1A2-mediated reactions. Part 1. Focusing on polycyclic arenes and the related chemicals.
This prediction system is based on placements of CYP1A2-substrates on a hexagonal-grid template in a way following the rule generated from the relationship of the substrate-structure and selective-area uses on the template, and also the rule for a triggering-event to initiate the catalytic reactions. Clear relationship found between the placements and preferred-order of regioselective reactions from the comparison of experimental data of polyaromatic hydrocarbon (PAH)-substrates was implemented in this system. The template generated is consisted of two flat-shape regions (Thin- and Thick-Areas) and Site of Oxidation. The latter is located at an overlapping region of Thin- and Thick-Areas and has a shape of cubic-like block. Thin-Area and Thick-Area are not on the same plane, and bend slightly at their overlapping parts. Two Entrances and two Gatekeepers are situated each near the top and middle bottleneck-parts of Thin-Area and Thick-Area to restrict the substrate entry. A procedure of stepwise movement of substrates resided on Thick-Area is introduced to define the regioselectivity. A specific part (termed Trigger-Region) showing high placement rates was found at a region away from Site of Oxidation on the template, assuming that substrate-sittings at Trigger-Region are essential for the initiation of catalytic reactions. These observations lead us an idea of simultaneous bi-molecule placement to fulfill both the essential sitting at Trigger-Region and regioselectivity of metabolisms, although a uni-molecule sitting co-covering Trigger-Region is also possible to contribute for the metabolite formation. Substrates of CYP1A2 are verified from distinct points including selective use of Thin-Area, Trigger-molecule Harboring Area, dual access routs, Facial-side Movement as well as their sizes. In addition, inhibitory actions as well region/stereo selective oxid/reductions of both PAH and non-PAH molecules are verified with their supposable interaction mechanisms in this prediction system.
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan; Food Safety Commission, Cabinet Office, Government of Japan, Japan. Electronic address: yamazoe@m.tohoku.ac.jp.
Yasushi
Y
Yamazoe
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.
Kazumi
K
Ito
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.
Yoshiya
Y
Yamamura
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan.
Ryutaro
R
Iwama
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan; Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Japan.
Kouichi
K
Yoshinari
D001665:Binding Sites / Q000502:physiology; D002384:Catalysis; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010084:Oxidation-Reduction; D013379:Substrate Specificity / Q000502:physiology
C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2
Grid template-based evaluation; Mechanism of inhibition; Multistep interactions of substrates; Prediction of occurrence order of the metabolism; Regio- and stereo-selective metabolism; Simulation of human CYP1A2 interaction