**Irina F. Sevrioukova**

Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697-3900, USA; sevrioui@uci.edu

Received: 9 August 2019; Accepted: 29 August 2019; Published: 30 August 2019

**Abstract:** 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insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6- ,7- -dihydroxybergamottin.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.

**Keywords:** CYP3A4; mechanism-based inhibitor; crystal structure
