Substrate selectivity of drug-metabolizing cytochrome P450s predicted from crystal structures and in silico modeling.

Abstract:

:Enormous efforts toward predicting the metabolic fate of a drug have been driven by the high attrition rate in drug development. To accelerate such efforts, it is critical to elucidate the molecular mechanisms of drug recognition by drug-metabolizing enzymes. Therefore, it is not surprising that an increasing number of crystal structures have been determined (by X-ray crystallography) and numerous insightful in silico (computational) models have been established for the most important metabolic enzymes, cytochrome P450s (CYPs). In this review, we provide a detailed analysis of the available crystal structures for CYPs to reveal the structural features and protein flexibility determining substrate selectivity. The ligand-based in silico models (including pharmacophore and molecular field analysis models) are also discussed, with a focus on their ability to characterize the structural features of the substrates for various CYP isoforms.

journal_name

Drug Metab Rev

journal_title

Drug metabolism reviews

authors

Dong D,Wu B

doi

10.3109/03602532.2011.645581

subject

Has Abstract

pub_date

2012-02-01 00:00:00

pages

1-17

issue

1

eissn

0360-2532

issn

1097-9883

journal_volume

44

pub_type

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