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分枝杆菌烯酰酰基辅酶 A 还原酶(InhA):抗结核药物发现的关键靶标。

Mycobacterium enoyl acyl carrier protein reductase (InhA): A key target for antitubercular drug discovery.

机构信息

Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur 440033, MS, India.

Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune 411018, Maharashtra, India.

出版信息

Bioorg Chem. 2021 Oct;115:105242. doi: 10.1016/j.bioorg.2021.105242. Epub 2021 Aug 8.

Abstract

Enoyl acyl carrier protein reductase (InhA) is a key enzyme involved in fatty acid synthesis mainly mycolic acid biosynthesis that is a part of NADH dependent acyl carrier protein reductase family. The aim of the present literature is to underline the different scaffolds or enzyme inhibitors that inhibit mycolic acid biosynthesis mainly cell wall synthesis by inhibiting enzyme InhA. Various scaffolds were identified based on the screening technologies like high throughput screening, encoded library technology, fragment-based screening. The compounds studied include indirect inhibitors (Isoniazid, Ethionamide, Prothionamide) and direct inhibitors (Triclosan/Diphenyl ethers, Pyrrolidine Carboxamides, Pyrroles, Acetamides, Thiadiazoles, Triazoles) with better efficacy against drug resistance. Out of the several scaffolds studied, pyrrolidine carboxamides were found to be the best molecules targeting InhA having good bioavailability properties and better MIC. This review provides with a detailed information, analysis, structure activity relationship and useful insight on various scaffolds as InhA inhibitors.

摘要

烯酰基辅酶 A 还原酶(InhA)是参与脂肪酸合成的关键酶,主要参与分枝菌酸生物合成,是 NADH 依赖的酰基辅酶 A 还原酶家族的一部分。本文献的目的是强调不同的支架或酶抑制剂,通过抑制酶 InhA 来抑制分枝菌酸生物合成,主要是细胞壁合成。各种支架是基于高通量筛选、编码文库技术、基于片段的筛选等筛选技术来识别的。研究的化合物包括间接抑制剂(异烟肼、乙胺丁醇、丙硫异烟胺)和直接抑制剂(三氯生/二苯醚、吡咯烷羧酰胺、吡咯、乙酰胺、噻二唑、三唑),对耐药性有更好的疗效。在研究的几种支架中,发现吡咯烷羧酰胺是针对 InhA 的最佳分子,具有良好的生物利用度特性和更好的 MIC。本综述提供了关于 InhA 抑制剂的各种支架的详细信息、分析、构效关系和有用的见解。

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