Get access

Probing ligand binding modes of human cytochrome P450 2J2 by homology modeling, molecular dynamics simulation, and flexible molecular docking

Authors

  • Weihua Li,

    1. School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
    Search for more papers by this author
  • Yun Tang,

    Corresponding author
    1. School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
    • School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China
    Search for more papers by this author
  • Hong Liu,

    1. Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
    Search for more papers by this author
  • Jiagao Cheng,

    1. School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
    Search for more papers by this author
  • Weiliang Zhu,

    1. Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
    Search for more papers by this author
  • Hualiang Jiang

    1. School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
    2. Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
    Search for more papers by this author

Abstract

Cytochrome P450 (P450) 2J2 catalyzes epoxidation of arachidonic acid to eicosatrienoic acids, which are related to a variety of diseases such as coronary artery disease, hypertension, and carcinogenesis. Recent experimental data also suggest that P450 2J2 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-dimensional 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 simulation. Flexible docking approaches were then employed to dock four ligands 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 residues responsible for substrate specificity were identified on the enzyme, which might be very helpful for understanding the enzyme's biological role and providing insights for designing novel inhibitors of P450 2J2. Proteins 2008. © 2007 Wiley-Liss, Inc.

Ancillary