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Biotransformation of Isoniazid by Cytochromes P450: Analyzing the Molecular Mechanism using Density Functional Theory
Chemical Research in Toxicology ( IF 4.1 ) Pub Date : 2017-10-16 00:00:00 , DOI: 10.1021/acs.chemrestox.7b00129
Chaitanya K. Jaladanki 1 , Akbar Shaikh 1 , Prasad V. Bharatam 1
Affiliation  

Hydrazide group (−C(O)–NH–NH2) is considered as a structural alert in the drug discovery process because the biotransformation chemistry of this group leads to the generation of toxic radical intermediates. The most important antitubercular drug isoniazid (INH) carries the hydrazide group. The toxicity of INH has been attributed to the protein adduct formation involving isonicotinoyl radical. However, the structures of reactive metabolites (RMs) and metabolite intermediate complexes (MICs), as well as the reaction mechanism for the formation and fate of RMs/MICs, have not been established. This report provides a detailed account of the biotransformation of INH by cytochromes using quantum chemical (QC) methods. Two cycles of cytochrome catalysis are involved in the formation of the most important RM, isonicotinoyl radical. The first cycle requires ∼11 kcal/mol barrier on the oxidation pathway involving the formation of the RM isonicotinoyldiazene. The second cycle involves a barrier of ∼7 kcal/mol for the activation of the diazene intermediate leading to isonicotinic acid via three reaction steps: (i) N–H bond activation, (ii) loss of N2 molecule, and (iii) rebound of isonicotinoyl radical. The RMs on the pathway (diazene, isonicotinoyl radical, N-hydroxy diazene) can react with the porphyrin ring/the amino acids of the cytochrome leading to many MICs (at least nine varieties), which can cause mechanism based inhibition and drug–drug interactions. This QC, molecular docking, and QM/MM study explored all the above reaction pathways and established the 3D structures of the RMs and MICs.

中文翻译:

细胞色素P450对异烟肼的生物转化:使用密度泛函理论分析分子机理

酰肼基(-C(O)–NH–NH 2)被认为是药物发现过程中的结构性预警,因为该组的生物转化化学导致有毒自由基中间体的产生。最重要的抗结核药物异烟肼(INH)带有酰肼基。INH的毒性已归因于涉及异烟酰基团的蛋白质加合物的形成。然而,尚未建立反应性代谢物(RMs)和代谢物中间体复合物(MICs)的结构,以及RMs / MICs的形成和命运的反应机理。本报告详细介绍了使用量子化学(QC)方法通过细胞色素对INH进行生物转化的过程。细胞色素催化的两个循环涉及最重要的RM异烟酰自由基的形成。第一个循环在涉及RM异烟酰基二氮烯形成的氧化途径上需要约11 kcal / mol的势垒。第二个循环涉及〜7 kcal / mol的势垒,用于通过三个反应步骤激活重氮中间体生成异烟酸的重氮中间体:(i)N–H键活化,(ii)N的损失2个分子,以及(iii)异烟酰基团的反弹。途径中的RM(二氮烯,异烟酰基,N-羟基重氮)可以与卟啉环/细胞色素的氨基酸反应,导致许多MIC(至少九种),这可能导致基于机制的抑制作用和药物作用互动。这项QC,分子对接和QM / MM研究探索了上述所有反应途径,并建立了RM和MIC的3D结构。
更新日期:2017-10-16
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