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Open AccessArticle

Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6′,7′-Dihydroxybergamottin

Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA
Int. J. Mol. Sci. 2019, 20(17), 4245;
Received: 9 August 2019 / Revised: 28 August 2019 / Accepted: 29 August 2019 / Published: 30 August 2019
(This article belongs to the Special Issue Cytochromes P450: Drug Metabolism, Bioactivation and Biodiversity 2.0)
Human cytochrome P450 3A4 (CYP3A4) is the most important drug-metabolizing enzyme. Some drugs and natural compounds can act as suicide (mechanism-based) inactivators of CYP3A4, leading to unanticipated drug-drug interactions, toxicity and therapeutic failures. Despite significant clinical and toxicological implications, the mechanism-based inactivation remains incompletely understood. This study provides the first direct insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6′,7′-dihydroxybergamottin. Novel structural findings help better understand the suicide substrate binding and inhibitory mechanism, and can be used to improve the predictability of the binding ability, metabolic sites and inhibitory/inactivation potential of newly developed drugs and other chemicals relevant to public health. View Full-Text
Keywords: CYP3A4; mechanism-based inhibitor; crystal structure CYP3A4; mechanism-based inhibitor; crystal structure
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MDPI and ACS Style

Sevrioukova, I.F. Structural Insights into the Interaction of Cytochrome P450 3A4 with Suicide Substrates: Mibefradil, Azamulin and 6′,7′-Dihydroxybergamottin. Int. J. Mol. Sci. 2019, 20, 4245.

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