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.

Keywords::

• Drug metabolism
• CYPs
• crystal structure
• in silico modeling
• pharmacophore
• CoMFA

Acknowledgment

The authors thank the reviewers’ valuable suggestion and comments.

Declaration of interest

Supported by the U.S. National Institutes of Health Grant RO1 ES012914 (to C.J.). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.