Structure - Function Analysis of the Cytochromes P450, Responsible for Phenprocoumon Metabolism

Israel Quiroga, Thomas Scior

Abstract


Phenprocoumon is an oral anticoagulant used for the prophylaxis and treatment of disorders due to thrombosis. However, if oral anticoagulants are not metabolized, they could exacerbate and generate clotting disorders. Phenprocoumon is metabolized by at least four hepatic enzymes members of the cytochromes P450 family; three of which are members of the same subfamily (CYP2C9, CYP2C19 and CYP2C8). Even with too many differences in their amino acid sequence and tertiary structures, CYP2C9 and CYP3A4 have the most similar metabolic activity on phenprocoumon. In this study, we were able to explain these activity similarities using force fields of molecular mechanics for geometry and energy optimization in combination with docking techniques. The results were compared to study Structure-Function Relationships (SFR) of our four target proteins (CYP2C9, CYP2C19, CYP2C8 and CYP3A4). The study and prediction of metabolism and sites of metabolisms of drugs was successfully performed using this approach.

Keywords


CYP450; CYP2C9; Structure-Function Relationship; Molecular Mechanics; Phenprocoumon; Docking; regioselectivity

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DOI: http://dx.doi.org/10.29356/jmcs.v61i4.466

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Journal of the Mexican Chemical Society (J. Mex. Chem. Soc.) Vol 62, No 2 (2018). Quarterly publication (April-June). Edited and distributed by Sociedad Química de México, A.C. Barranca del Muerto 26, Col. Crédito Constructor, Del. Benito Juárez, C.P. 03940, Mexico City. Phone: +5255 56626837; +5255 56626823 Contact: soquimex@sqm.org.mx http://www.sqm.org.mx Editor-in-Chief: Ignacio González-Martínez. Indexed Journal. Certificate of reserved rights for recurrent publications under digital distribution granted by the Instituto Nacional del Derecho de Autor (INDAUTOR): 04-2018-091118040000-203. Certificate of lawful title and content: Under procedure. ISSN-e granted by the Instituto Nacional del Derecho de Autor (INDAUTOR): 2594-0317. ISSN granted by the Instituto Nacional del Derecho de Autor (INDAUTOR): 1870-249X. Postal registration of printed matter deposited by editors or agents granted by SEPOMEX: IM09-0312 Copyright © Sociedad Química de México, A.C. Total or partial reproduction is prohibited without written permission of the right holder. The Figures/schemes quality and the general contents of this publication are full responsibility of the authors. Updated December 12th, 2018 by Adriana Vázquez (editorial assistant, e-mail: editor.jmcs@gmail.com), J. Mex. Chem. Soc., Sociedad Química de México, A.C.