Probing ligand binding modes of human cytochrome P45O SJS by homology modeling, molecular dynamics simulation,and flexible molecular docking

摘要

Cytochrome P450 (P450) 2J2 catalyzes epoxidation of arachidonic acid to eicosatrienoic acids, which are related to a variety of diseases such as coro nary artery disease, hypertension, and carcinogenesis. Recent experimental data also suggest that P450 2}2 could be a novel biomarker and a potential target for cancer therapy. However, the active site topology and substrate specificity of this enzyme remain unclear. In this study, a three-dimen sional model of human P450 2J2 was first constructed on the basis of the crystal structure of human P450 2C9 in complex with a substrate using homology modeling method, and refined by molecular dynamics simula tion. Flexible docking approaches were then employed to dock four Hgands into the active site of P450 2J2 in order to probe the ligand-binding modes. By analyzing the results, active site architecture and certain key resi dues responsible for substrate specific ity were identified on the enzyme, which might be very helpful for under standing the enzyme's biological role and providing insights for designing novel inhibitors of P450 2J2.