Tuberculosis (TB) remains a serious global health challenge that is caused by Mycobacterium tuberculosis and has killed numerous people. This necessitated the urgent need for the hunt and development of more potent drugs against the fast-emerging extensively drug-resistant (XDR) and multiple-drug-resistant (MDR) M. tuberculosis strains. Mycobacterium tuberculosis cytochrome b subunit of the cytochrome bc1 complex (QcrB) was recognized as a potential drug target in M. tuberculosis (25618/H37Rv) for imidazo[1,2-a]pyridine-3-carboxamides whose crystal strucuture is not yet reported in the Protein Data Bank (PDB). The concept of homology modeling as a powerful and useful computational method can be applied, since the M. tuberculosis QcrB protein sequence data are available. The homology model of QcrB protein in M. tuberculosis was built from the X-ray structure of QcrB in M. smegmatis as a template using the Swiss-Model online workspace. The modeled protein was assessed, validated, and prepared for the molecular docking simulation of 35 ligands of N-(2-phenoxy)ethyl imidazo[1,2-a] pyridine-3-carboxamide (IPA) to analyze their theoretical binding affinities and modes. The docking results showed that the binding affinity values ranged from − 6.5 to − 10.1 kcal/mol which confirms their resilience potency when compared with 6.0kcal/mol of isoniazid standard drug. However, ligands 2, 7, 22, 26, and 35 scored higher binding affinity values of − 9.60, − 9.80, − 10.10, − 10.00, and − 10.00 kcal/mol, and are respectively considered as the best ligands among others with better binding modes in the active site of the modeled QcrB protein. The information derived in this research revealed some potential hits and paved a route for structure-based drug discovery of new hypothetical imidazo pyridine amide analogs as anti-tubercular drug candidates.

中文翻译：

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一些新型咪唑并[1,2-a]吡啶-3-甲酰胺（IPA）系列作为结核分枝杆菌抑制剂的同源建模和分子对接模拟


结核病 (TB) 仍然是一个严重的全球健康挑战，由结核分枝杆菌引起，已导致无数人死亡。这就迫切需要寻找和开发更有效的药物来对抗快速出现的广泛耐药（XDR）和多重耐药（MDR）结核分枝杆菌菌株。结核分枝杆菌细胞色素 bc1 复合物的细胞色素 b 亚基 (QcrB) 被认为是结核分枝杆菌 (25618/H37Rv) 中咪唑并[1,2-a]吡啶-3-甲酰胺的潜在药物靶点，其晶体结构尚未报道在蛋白质数据库（PDB）中。由于结核分枝杆菌 QcrB 蛋白序列数据是可用的，因此可以应用同源建模的概念作为一种强大且有用的计算方法。结核分枝杆菌中 QcrB 蛋白的同源模型是以耻垢分枝杆菌中 QcrB 的 X 射线结构为模板，使用 Swiss-Model 在线工作区构建的。对模型蛋白进行了评估、验证和准备，用于 N-(2-苯氧基)乙基咪唑并[1,2-a]吡啶-3-甲酰胺 (IPA) 的 35 个配体的分子对接模拟，以分析它们的理论结合亲和力和模式。对接结果显示，结合亲和力值范围为- 6.5至- 10.1 kcal/mol，这证​​实了与异烟肼标准药物的6.0 kcal/mol相比，它们的恢复能力。然而，配体2、7、22、26和35的结合亲和力值较高，分别为- 9.60、- 9.80、- 10.10、- 10.00和- 10.00 kcal/mol，并分别被认为是最佳配体，具有更好的结合力。模拟 QcrB 蛋白活性位点的结合模式。 这项研究中获得的信息揭示了一些潜在的成果，并为基于结构的药物发现新假设的咪唑并吡啶酰胺类似物作为抗结核候选药物铺平了道路。