Cytochrome homology modelling

S Modi, MI Paine, MI Sutcliffe, L-Y Lian, WU Pnmi-ose, CR Wolfe, GCK Roberts. A model for human cytochrome P450 2d6 based on homology modeling and NMR studies of substrate binding. Biochemistry 35 4540-4550, 1996. 

Koymans LMH, Vermeulen NPE, Baarslag A, Donne-Op den Kelder GM. A preliminary 3D model for cytochrome P450 2D6 constructed by homology model building. J Comput-Aided Mol Des 1993 7 281-9. 

Szklarz GD, Halpert JR. Use of homology modeling in conjunction with site-directed mutagenesis for analysis of structure-function relationships of mammalian cytochromes P450. Life Sci 1997 61 2507-20. 

Wang Q, Halpert JR. Combined three-dimensional qnantitative strnctnre-activity relationship analysis of cytochrome P450 2B6 snbstrates and protein homology modeling. Drug Metab Dispos 2002 30 86-95. 

The protein factor in MetaSite is based on homology models of the CYP450s, but it offers the possibility for the user to introduce any CYP450 structure. Several analyses have been done comparing the results obtained using the crystal structures and the homology models of the cytochromes. 

Key Words CYP P450 cytochrome P450 docking structure-based drug discovery pharmacophore QSAR homology models databases computational models ADME/T. 

Lewis, D. F. V. (1999) Homology modelling of human cytochromes P450 involved in xenobiotic metabolism and rationalization of substrate selectivity. Exp. Toxicol. Pathol. 51, 369-374. 

In a similar vein, homology modelling has been extensively used to derive 3D active site models for several cytochromes of the extensive P450 family, based on the high-resolution crystal structure of the bacterial P450cam (P-450-101) as template (Lewis and Moereels, 1992 Koymans et al., 1993b). These models have been used to explain substrate specificity. 

Venhorst J, ter Laak AM, Commandeur JN, et al. Homology modeling of rat and human cytochrome P450 2D (CYP2D) isoforms and computational rationalization of experimental ligand-binding specificities. J Med Chem 2003 46 74—86. 

Jean P, Pothier J, Dansette PM, et al. Automated multiple analysis of protein structures application to homology modeling of cytochromes P450. Proteins 1997 28 388-404. 

Szklarz GD, Ornstein RL, Halpert JR. Application of 3-dimensional homology modeling of cytochrome P450 2B1 for interpretation of site-directed mutagenesis results. J Biomol Struct Dyn 1994 12 61-78. 

M. Ridderstrom, I. Zamora, O. Fjell-strom, T. B. Andersson, Analysis of selective regions in the active sites of human cytochromes P450, 2C8, 2C9, 2C18, and 2C19 homology models... 

The Pathfinder approach was used to compare the CYP cavities of CYP2C9 [8], 2D6 [9], and 3A4 [10], the most important human cytochrome enzymes. CYP2C9 and 3A4 were available as protein crystal structures whilst an homology model was used for 2D6. Frequency distribution plots (Fig. 5.8) were obtained from non-superposed CYP structures, selecting the iron in the heme moiety as a root departure path. 

The aim of the present chapter is to describe a recent in silico method. It is fast, easy and computationally inexpensive, and able to predict human cytochrome regioselective metabolism using ad hoc developed 3D homology models for the enzymes and the 3D structure of the potential substrates. The method uses GRID flexible molecular interaction fields as well as the 3D structure of the potential substrates, automatically providing the site of metabolism (i.e. the place where the metabolic reactions occur) in graphical output. 

---