Impact of electrostatic distribution in CYP3A4 on the regioselectivity of triazolam metabolism and regulation of its metabolic rate by the iron spin states: Insights from MD simulations and QM calculations
文献类型：期刊论文
| 作者 | Zhao, Yan2; Ma, Xinyu1,3; Zheng, Qingchuan2,4 |
| 刊名 | JOURNAL OF INORGANIC BIOCHEMISTRY
 |
| 出版日期 | 2026-03-01 |
| 卷号 | 276页码:12 |
| 关键词 | Triazolam Cytochrome P450 enzyme Regioselectivity Metabolic mechanism MD simulation QM calculation |
| ISSN号 | 0162-0134 |
| DOI | 10.1016/j.jinorgbio.2025.113162 |
| 通讯作者 | Zheng, Qingchuan(zhengqc@jlu.edu.cn) |
| 英文摘要 | 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 it-it 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 C alpha-H serving as the key metabolic site and CYP3A4-catalyzed C alpha-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 highspin state appears to accelerate TRZ metabolism, potentially leading to the accumulation of alpha-OH triazolam in vivo, which may pose risks to human health. These results could enhance our understanding of CYP3A4mediated regioselective metabolism of TRZ and provide a theoretical foundation and new perspective for studies on the metabolism of other triazole drugs. |
| WOS关键词 | ACCELERATED MOLECULAR-DYNAMICS ; COMPOUND-I ; SUBSTRATE RECOGNITION ; BENZODIAZEPINE USE ; CYTOCHROME-P450 ; HYDROXYLATION ; MODEL ; BOND ; SITE ; ABSTRACTION |
| 资助项目 | National Natural Science Foundation of China[22073036] ; The Medicine + X Interdisciplinary Innovation Team of Norman Bethune Health Science Center of Jilin University[2025JBGS08] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:001633144300002 |
| 出版者 | ELSEVIER SCIENCE INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322354]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zheng, Qingchuan |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Jilin Univ, Inst Frontier Med Sci, Sch Pharmaceut Sci, Changchun 130023, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 4.Jilin Univ, Inst Theoret Chem, Coll Chem, Changchun 130023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhao, Yan,Ma, Xinyu,Zheng, Qingchuan. Impact of electrostatic distribution in CYP3A4 on the regioselectivity of triazolam metabolism and regulation of its metabolic rate by the iron spin states: Insights from MD simulations and QM calculations[J]. JOURNAL OF INORGANIC BIOCHEMISTRY,2026,276:12. |
| APA | Zhao, Yan,Ma, Xinyu,&Zheng, Qingchuan.(2026).Impact of electrostatic distribution in CYP3A4 on the regioselectivity of triazolam metabolism and regulation of its metabolic rate by the iron spin states: Insights from MD simulations and QM calculations.JOURNAL OF INORGANIC BIOCHEMISTRY,276,12. |
| MLA | Zhao, Yan,et al."Impact of electrostatic distribution in CYP3A4 on the regioselectivity of triazolam metabolism and regulation of its metabolic rate by the iron spin states: Insights from MD simulations and QM calculations".JOURNAL OF INORGANIC BIOCHEMISTRY 276(2026):12. |
入库方式： OAI收割
来源：上海药物研究所
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