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-羧酰胺（IPA）系列作为结核分枝杆菌抑制剂的同源性建模和分子对接模拟

结核病（TB）仍然是由结核分枝杆菌引起的严重的全球健康挑战，已经杀死了许多人。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性（XDR）和多重耐药性（MDR）的结核分枝杆菌菌株。细胞色素bc1复合物（QcrB）的结核分枝杆菌细胞色素b亚基被认为是结核分枝杆菌（25618 / H37Rv）潜在的药物靶标，其咪唑[1,2-a]吡啶-3-羧酰胺的晶体结构尚未报道在蛋白质数据库（PDB）中。由于可获得结核分枝杆菌QcrB蛋白序列数据，因此可以应用同源性建模作为一种强大而有用的计算方法的概念。拟南芥QcrB蛋白同源模型。结核病是使用瑞士模式在线工作区，以耻垢分枝杆菌中QcrB的X射线结构为模板建立的。对建模的蛋白质进行评估，验证和制备，以用于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，以分析其理论结合亲和力和模式。对接结果表明，结合亲和力值在-6.5至-10.1 kcal / mol的范围内，与异烟肼标准药物6.0kcal / mol的结合力相比，证实了它们的弹性。但是，配体2、7、22、26和35的结合亲和力值分别为-9.60，-9.80，-10.10，-10.00和-10.00 kcal / mol，它们分别被认为是最佳的配体，具有更好的配体。 QcrB蛋白活性位点中的结合模式。