title: Characterization of the CYP3A4 active site by homology modeling.
abstract: Human microsomal cytochrome P450s participate in drug metabolism and detoxification. Among them, CYP3A4 is the most important isoform for drug-drug interactions. To gain a better understanding of the active site, a homology model of CYP3A4 was constructed based on the crystallographic coordinates of mammalian CYP2C5. The putative active site is much larger than that of CYP2C5 and is divided into three parts (i.e. a proximal and two distal sites from the heme). Most residues reported to be important for ligand-binding are located in the active site of the model. Moreover, some inhibitors (paclitaxel etc.) docked into the model have complementary shapes to the pocket. Pharmacophore docking of 14 substrates was also performed using Ph4Dock of MOE. Calculated interaction energies showed a moderate correlation with the logarithm of apparent K(m) values. These results suggest that this model is reliable enough to be used in the design of compounds for removing undesirable CYP3A4 inhibition.
authors.affiliation: Pharmaceutical Research Division, Takeda Chemical Industries, Ltd. Osaka, Japan. Tanaka_Toshimasa@takeda.co.jp
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Teruaki
authors.initials: T
authors.lastname: Okuda
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamamoto
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013255:Steroid 21-Hydroxylase / Q000737:chemistry
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; C065407:CYP2C5 protein, Oryctolagus cuniculus; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D013255:Steroid 21-Hydroxylase; C510163:CYP3A4 protein, human