Panda Debashis, Maharana Jitendra, Sharma Arjun, Wadavrao Sachin B, Chowdhury Abhishek, Laskar Monjur Ahmed, Modi Mahendra K, Choudhury Manabendra D
Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, 788011, India.
DBT-APSCS&T Centre of Excellence for Bioresources and Sustainable Development, Kimin, Arunachal Pradesh, 791121, India.
Mol Divers. 2025 May 13. doi: 10.1007/s11030-025-11205-7.
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.
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，凸显了探索新型治疗药物的迫切需求。分枝菌酸是细菌细胞壁形成所必需的，由两种脂肪酸合酶（FAS）系统合成：FAS-I和FAS-II。MabA是FAS-II系统中的一种酶，在脂肪酸生物合成的第二步中至关重要，负责分枝菌酸的延长。在本研究中，我们从七个不同数据库中筛选了1,792,771种化合物，以筛选MabA的潜在抑制剂，MabA是Mtb的一个新兴治疗靶点。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，我们从五个不同类别中鉴定出48种新型先导化合物，它们对MabA表现出显著的结合活性。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，我们的研究结果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型疗法方面取得了重大进展。
