title: Theoretical investigation of substrate specificity for cytochromes P450 IA2, P450 IID6 and P450 IIIA4.
abstract: Three-dimensional models of the cytochromes P450 IA2, P450 IID6 and P450 IIIA4 were built by means of comparative modeling using the X-ray crystallographic structures of P450 CAM, P450 BM-3, P450 TERP and P450 ERYF as templates. The three cytochromes were analyzed both in their intrinsic structural features and in their interaction properties with fifty specific and non-specific substrates. Substrate/enzyme complexes were obtained by means of both automated rigid and flexible body docking. The comparative analysis of the three cytochromes and the selected substrates, in their free and bound forms, allowed for the building of semi-quantitative models of substrate specificity based on both molecular and intermolecular interaction descriptors. The results of this study provide new insights into the molecular determinants of substrate specificity for the three different eukaryotic P450 isozymes and constitute a useful tool for predicting the specificity of new compounds.
authors.affiliation: Dipartimento di Chimica, Università di Modena e Reggio Emilia, Italy.
authors.forename: F
authors.initials: F
authors.lastname: De Rienzo
authors.forename: F
authors.initials: F
authors.lastname: Fanelli
authors.forename: M C
authors.initials: MC
authors.lastname: Menziani
authors.forename: P G
authors.initials: PG
authors.lastname: De Benedetti
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D008861:Microsomes / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D013816:Thermodynamics
chemical_list: D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A