Crystallization homology modeling

Statistical, Pharmacophore, and Homology Models and Crystal Structures of Drug-Metabolizing Enzymes... 

STATISTICAL, PHARMACOPHORE, AND HOMOLOGY MODELS AND CRYSTAL STRUCTURES OF DRUG-METABOLIZING ENZYMES... 

Enzyme Cellular Location Reaction Cofactor Phase OSAR Pharmacophore Homology models Crystal structures... 

D CRYSTAL STRUCTURES HOMOLOGY MODELLING MOLECULAR SIMILARITY ... 

Cruciani et al. [92] have developed the program Metasite for the prediction of the site of oxidative metabolism by CYP450 enzymes. Metasite uses GRID molecular interaction fields to fingerprint both structures of CYP450s (from homology models or crystal structures) and test substrates and then matches the fields. Zhou et al. [93] showed that Metasite was able to correctly predict the site(s) of metabolism 78% of the time for 227 CYP3A4 substrates. Caron et al. [94] used Metasite to predict the oxidative metabolism of seven statins. 

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. 

Kjellander, B., Masimirembwa, C.M. and Zamora, I. (2007) Exploration of enzyme-ligand interactions in CYP2D6 3A4 homology models and crystal structures using a novel computational approach. Journal of Chemical Information and Modeling, 47 (3), 1234-1247. 

Before the elucidation of the CAR X-ray crystal structure, modeling studies mainly focused on the constitutive activity of the receptor. For example, homology modeling along with molecular dynamics simulations was combined to identify critical amino acid residues responsible for the constitutive activation [43]. Especially, the role of Tyr326 as a molecular mimicry of a bound ligand in the interaction with the AF-2 helix was underscored. Mutational analyses and the later elucidation of the human CAR X-ray crystal structure confirmed an important role of this amino acid for the receptor s constitutive activity [41,44]. 

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