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Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

In Silico Modeling of P450 Substrates, Inhibitors, Activators, and Inducers

Author(s): Robert Kirk DeLisle, Jennifer Otten and Susan Rhodes

Volume 14, Issue 5, 2011

Page: [396 - 416] Pages: 21

DOI: 10.2174/138620711795508377

Price: $65

Abstract

Cytochrome P450 enzymes are the predominant mediators of phase I metabolism of exogenous small molecules. As a result of their extensive role in metabolism of xenobiotics, drug compounds, and endogenous compounds, as well as their wide tissue distribution, significant drug discovery resources are spent to avoid interacting with this class of enzymes. Here we review historical and recent in silico modeling of 7 cytochrome P450 enzymes of particular interest, specifically CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. For each we provide a brief biological background including known inhibitors, substrates, and inducers, as well as details of computational modeling efforts and advances in structural biology. We also provide similar details for 3 nuclear receptors known to regulate gene expression of these enzyme families.

Keywords: Cytochrome P450, molecular modeling, drug metabolism, Substrates, Inhibitors, Activators, Inducers, exogenous small molecules, structural biology


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