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insights into the interaction of CYP3A4 with three suicide substrates: mibefradil, an antihypertensive drug quickly withdrawn from the market; a semi-synthetic antibiotic azamulin; and a natural furanocoumarin, 6′,7′-dihydroxybergamottin.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.
Highlights
Human cytochrome P450 3A4 (CYP3A4) oxidizes over 50% of administered drugs [1], along with natural compounds, some of which can act as inhibitors of CYP3A4 [2]
The mechanism-based inhibition (MBI) of CYP3A4 is the most common mechanism that could lead to clinically significant drug-drug interactions (DDIs), toxicity and therapeutic failures [3]
To fill this knowledge gap, this study investigated the binding manner of mibefradil, azamulin, bergamottin and 6,7 -dihydroxybergamottin (DHB) (Figure 1), which are known to act as potent mechanism-based inhibitors of CYP3A4
Summary
Human cytochrome P450 3A4 (CYP3A4) oxidizes over 50% of administered drugs [1], along with natural compounds, some of which can act as inhibitors of CYP3A4 [2]. The early elimination of the MBI/DDI potential in drug candidates is crucial [4] but highly challenging due to poor predictability of CYP3A4-ligand interactions This results from high promiscuity [5] and conformational flexibility of CYP3A4 [6,7,8] and very limited structural information on the substrate association modes. Only three crystal structures of CYP3A4 with drug substrates bound in the active site have been reported [6,7,9] and none with suicide inactivators To fill this knowledge gap, this study investigated the binding manner of mibefradil, azamulin, bergamottin and 6 ,7 -dihydroxybergamottin (DHB) (Figure 1), which are known to act as potent mechanism-based inhibitors of CYP3A4.
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