Issue 3, 2016

Effects of protein flexibility and active site water molecules on the prediction of sites of metabolism for cytochrome P450 2C19 substrates

Abstract

Structure-based prediction of sites of metabolism (SOMs) mediated by cytochrome P450s (CYPs) is of great interest in drug discovery and development. However, protein flexibility and active site water molecules remain a challenge for accurate SOM prediction. CYP2C19 is one of the major drug-metabolizing enzymes and has attracted considerable attention because of its polymorphism and capability of metabolizing ∼7% clinically used drugs. In this study, we systematically evaluated the effects of protein flexibility and active site water molecules on SOM prediction for CYP2C19 substrates. Multiple conformational sampling techniques including GOLD flexible residues sampling, molecular dynamics (MD) and tCONCOORD side-chain sampling were adopted for assessing the influence of protein flexibility on SOM prediction. The prediction accuracy could be significantly improved when protein flexibility was considered using the tCONCOORD sampling method, which indicated that the side-chain conformation was important for accurate prediction. However, the inclusion of the crystallographic or MD-derived water molecule(s) does not necessarily improve the prediction accuracy. Finally, a combination of docking results with SMARTCyp was found to be able to increase the SOM prediction accuracy.

Graphical abstract: Effects of protein flexibility and active site water molecules on the prediction of sites of metabolism for cytochrome P450 2C19 substrates

Supplementary files

Article information

Article type
Paper
Submitted
15 Nov 2015
Accepted
05 Jan 2016
First published
05 Jan 2016

Mol. BioSyst., 2016,12, 868-878

Effects of protein flexibility and active site water molecules on the prediction of sites of metabolism for cytochrome P450 2C19 substrates

J. Li, J. Cai, H. Su, H. Du, J. Zhang, S. Ding, G. Liu, Y. Tang and W. Li, Mol. BioSyst., 2016, 12, 868 DOI: 10.1039/C5MB00784D

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Spotlight

Advertisements