Identifying potent inhibitors for Mycobacterium tuberculosis MabA (FabG1).

IF 3.9 2区化学 Q2 CHEMISTRY, APPLIED

Molecular Diversity Pub Date : 2025-05-13 DOI:10.1007/s11030-025-11205-7

Debashis Panda, Jitendra Maharana, Arjun Sharma, Sachin B Wadavrao, Abhishek Chowdhury, Monjur Ahmed Laskar, Mahendra K Modi, Manabendra D Choudhury

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引用次数: 0

Abstract

The surge in drug-resistant Mycobacterium tuberculosis (Mtb) strains poses formidable challenges for tuberculosis treatment, emphasizing the pressing need to explore novel therapeutic agents. Mycolic acids, essential for bacterial cell wall formation, are synthesized by two fatty acid synthase (FAS) systems: FAS-I and FAS-II. MabA, an enzyme in the FAS-II system, is vital in the second step of fatty acid biosynthesis and is responsible for the elongation of mycolic acids. In this study, we screened 1,792,771 compounds from seven different databases to screen prospective inhibitors of MabA, an emerging therapeutic target for Mtb. Using a combination of molecular docking, all-atom molecular dynamics simulations, and binding free energy calculations, we identified 48 novel lead compounds from five distinct classes that exhibit significant binding activity against MabA. Of these, 47 compounds demonstrated significantly higher MM/PBSA binding free energy than the only reported MabA inhibitor, compound 29. Altogether, our findings mark a significant advancement towards the rational design of novel therapeutics aimed at combating mycobacterial infections and overcoming drug resistance.

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鉴定结核分枝杆菌MabA （FabG1）的有效抑制剂。

耐药结核分枝杆菌（Mtb）菌株的激增给结核病治疗带来了巨大挑战，强调迫切需要探索新的治疗药物。霉菌酸是细菌细胞壁形成所必需的，由两种脂肪酸合成酶（FAS）系统：FAS- i和FAS- ii合成。maa是FAS-II系统中的一种酶，在脂肪酸生物合成的第二步中起着至关重要的作用，并负责霉菌酸的延伸。在这项研究中，我们从7个不同的数据库中筛选了1,792,771种化合物，以筛选MabA的预期抑制剂，MabA是结核分枝杆菌的新兴治疗靶点。通过结合分子对接、全原子分子动力学模拟和结合自由能计算，我们从5个不同的类别中鉴定出48种新的先导化合物，它们对maa具有显著的结合活性。其中，47种化合物的MM/PBSA结合自由能明显高于唯一报道的MabA抑制剂化合物29。总之，我们的发现标志着在合理设计旨在对抗分枝杆菌感染和克服耐药性的新疗法方面取得了重大进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Diversity 化学-化学综合

CiteScore

7.30

自引率

7.90%

发文量

219

审稿时长

2.7 months

期刊介绍： Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including: combinatorial chemistry and parallel synthesis; small molecule libraries; microwave synthesis; flow synthesis; fluorous synthesis; diversity oriented synthesis (DOS); nanoreactors; click chemistry; multiplex technologies; fragment- and ligand-based design; structure/function/SAR; computational chemistry and molecular design; chemoinformatics; screening techniques and screening interfaces; analytical and purification methods; robotics, automation and miniaturization; targeted libraries; display libraries; peptides and peptoids; proteins; oligonucleotides; carbohydrates; natural diversity; new methods of library formulation and deconvolution; directed evolution, origin of life and recombination; search techniques, landscapes, random chemistry and more;