Triazolam (TRZ) is a representative benzodiazepine sedative-hypnotic drug that has gradually been abused due to the increasing societal pressures. To further provide a theoretical basis for the rationale use of TRZ and obtain more information for its metabolic process, in this study, human CYP3A4 was employed as the metabolic enzyme to investigate the metabolic mechanism of TRZ by multiple computational methods. Here, three types of substrate-binding conformations related to the diversity of TRZ metabolites are identified (pose A, pose B and pose C). The “sandwich” structure and the π-π stacking between TRZ and F304/porphyrin ring may be the key factors in dominating three substrate-binding conformations. Furthermore, we discovered pose A is the predominant binding mode, with Cα-H serving as the key metabolic site and CYP3A4-catalyzed Cα-H hydroxylation follows a hydrogen abstraction-rebound mechanism. More importantly, in hydroxylation process, the spin states of iron can regulate the metabolic reaction rate of TRZ and the highest rate of metabolism (5.96 s−1) is found in the quartet spin states. Based on our findings, it can be suggested that rational incorporating aromatic groups into TRZ could improve its metabolic stability. Meanwhile, the transition of the heme iron from a low-spin to a high-spin state appears to accelerate TRZ metabolism, potentially leading to the accumulation of α-OH triazolam in vivo, which may pose risks to human health. These results could enhance our understanding of CYP3A4-mediated regioselective metabolism of TRZ and provide a theoretical foundation and new perspective for studies on the metabolism of other triazole drugs.
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