Molecular modeling on inhibitor complexes and active-site dynamics of cytochrome P450 C17, a target for prostate cancer therapy.

Haider, S.M., Patel, J., Poojari, C. and Neidle, S. (2010) Molecular modeling on inhibitor complexes and active-site dynamics of cytochrome P450 C17, a target for prostate cancer therapy. Journal of Molecular Biology, 400 (5). pp. 1078-1098. 10.1016/j.jmb.2010.05.069 .

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DOI: 10.1016/j.jmb.2010.05.069

Abstract

A molecular model for the P450 enzyme cytochrome P450 C17 (CYP17) is presented based on sequence alignments of multiple template structures and homology modeling. This enzyme plays a central role in the biosynthesis of testosterone and is emerging as a major target in prostate cancer, with the recently developed inhibitor abiraterone currently in advanced clinical trials. The model is described in detail, together with its validation, by providing structural explanations to available site-directed mutagenesis data. The CYP17 molecule in this model is in the form of a triangular prism, with an edge of approximately 55 A and a thickness of approximately 37 A. It is predominantly helical, comprising 13 alpha helices interspersed by six 3(10) helices and 11 beta-sheets. Multinanosecond molecular dynamics simulations in explicit solvent have been carried out, and principal components analysis has been used to reveal the details of dynamics around the active site. Coarse-grained methods have also been used to verify low-frequency motions, which have been correlated with active-site gating. The work also describes the results of docking synthetic inhibitors, including the drug abiraterone and the natural substrate pregnenolone, in the CYP17 active site together with molecular dynamics simulations on the complexes.

Item Type:Article
Additional Information:Full text available electronically from the School of Pharmacy Library.
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Cancer Research UK Biomolecular Structure Group
ID Code:1684
Journal or Publication Title:Journal of Molecular Biology
Deposited By:Library Staff
Deposited On:03 Aug 2010 15:17
Last Modified:04 Feb 2011 12:46

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