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International Journal of Medicinal Chemistry
Volume 2011, Article ID 918168, 11 pages
http://dx.doi.org/10.1155/2011/918168
Research Article

Studies on 16α-Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11

1Faculty of Pharmacy, Helwan University, Ain Helwan, Cairo 11795, Egypt
2Department of Chemistry, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
3Liberal Arts Center, Hyogo University of Health Sciences, 1-3-6, Minatojima, Chuo-ku, Kobe 650-8530, Japan
4Faculty of Pharmaceutical Sciences, Center for Area Research and Development (CARD), Kobe Gakuin University, 1-1-3, Minatojima, Chuo-ku, Kobe 650-8586, Japan

Received 8 December 2009; Revised 14 June 2010; Accepted 2 July 2010

Academic Editor: Edith Sim

Copyright © 2011 Hamed I. Ali et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We investigated the 16α-hydroxylation of steroid molecules and regioselective binding mode in homology-modeled cytochrome P450-2C11 to correlate the biological study with the computational molecular modeling. It revealed that there was a positive relationship between the observed inhibitory potencies and the binding free energies. Docking of steroid molecules into this homology-modeled CYP2C11 indicated that 16α-hydroxylation is favored with steroidal molecules possessing the following components, (1) a bent A-B ring configuration (5β-reduced), (2) C-3 α-hydroxyl group, (3) C-17β-acetyl group, and (4) methyl group at both the C-18 and C-19. These respective steroid components requirements were defined as the inhibitory contribution factor. Overall studies of the male rat CYP2C11 metabolism revealed that the above-mentioned steroid components requirements were essential to induce an effective inhibition of [3H]progesterone 16α-hydroxylation. As far as docking of homology-modeled CYP2C11 against investigated steroids is concerned, they are docked at the active site superimposed with flurbiprofen. It was also found that the distance between heme iron and C16α-H was between 4 to 6 Å and that the related angle was in the range of 180±45.