Molecular modeling of human cytochrome P450-substrate interactions

The results of homology modeling of 10 human cytochrome P450 (CYP) enzymes involved in the Phase 1 metabolism of drugs and other foreign compounds are reported. The models have been constructed from the CYP102 hemoprotein domain template for which the substrate-bound crystallographic coordinates are...

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Bibliographic Details
Published in:Drug metabolism reviews 2002-01, Vol.34 (1-2), p.55-67
Main Author: Lewis, David F. V.
Format: Article
Language:English
Subjects:
Cytochrome P-450 Enzyme System - chemistry
Cytochrome P-450 Enzyme System - metabolism
Humans
Isoenzymes - chemistry
Isoenzymes - metabolism
Models, Molecular
Models, Theoretical
Quantitative Structure-Activity Relationship
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Summary:The results of homology modeling of 10 human cytochrome P450 (CYP) enzymes involved in the Phase 1 metabolism of drugs and other foreign compounds are reported. The models have been constructed from the CYP102 hemoprotein domain template for which the substrate-bound crystallographic coordinates are available. Selective substrates of individual human P450s: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11 are all shown to fit within the corresponding enzymes' active sites in such a manner that is consistent with reported experimental data for both known pathways of substrate metabolism and from the results of site-directed mutagenesis, either in those particular human P450 enzymes concerned or for ones within the same subfamily. The self-consistency of these homology models indicates that they may have potential utility for the pre-screening of novel drug structures.
ISSN:0360-2532
1097-9883
DOI:10.1081/DMR-120001390