Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, 500078, India.
School of Chemistry and Molecular Biosciences and Australian Infectious Disease Research Centre, The University of Queensland, Brisbane, Australia.
J Comput Aided Mol Des. 2019 Mar;33(3):357-366. doi: 10.1007/s10822-019-00184-1. Epub 2019 Jan 21.
Tuberculosis (TB) remains a major threat to human health. This due to the fact that current drug treatments are less than optimal and the increasing occurrence of multi drug-resistant strains of etiological agent, Mycobacterium tuberculosis (Mt). Given the wide-spread significance of this disease, we have undertaken a design and evaluation program to discover new anti-TB drug leads. Here, we focused on ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway. Importantly, this enzyme is present in bacteria but not in humans, making it an attractive proposition for drug discovery. In the present work, we used molecular docking to identify seventeen potential inhibitors of KARI using an in-house database. Compounds were selected based on docking scores, which were assigned as the result of favourable interactions between the compound and the active site of KARI. The inhibitory constant values for two leads, compounds 14 and 16 are 3.71 and 3.06 µM respectively. To assess the mode of binding, 100 ns molecular dynamics simulations for these two compounds in association with Mt KARI were performed and showed that the complex was stable with an average root mean square deviation of less than 3.5 Å for all atoms. Furthermore, compound 16 showed a minimum inhibitory concentration of 2.06 ± 0.91 µM and a 1.9 fold logarithmic reduction in the growth of Mt in an infected macrophage model. The two compounds exhibited low toxicity against RAW 264.7 cell lines. Thus, both compounds are promising candidates for development as an anti-TB drug leads.
结核病（TB）仍然是人类健康的主要威胁。这是由于目前的药物治疗效果不理想，以及引起疾病的结核分枝杆菌（Mt）的多药耐药菌株的发生率不断增加。鉴于这种疾病的广泛意义，我们已经开展了一项设计和评估计划，以发现新的抗结核药物先导物。在这里，我们专注于酮酸还原异构酶（KARI），支链氨基酸生物合成途径中的第二种酶。重要的是，这种酶存在于细菌中而不存在于人体中，因此它是药物发现的一个有吸引力的提议。在目前的工作中，我们使用分子对接技术，使用内部数据库识别了十七种潜在的 KARI 抑制剂。化合物是根据对接分数选择的，这些分数是化合物与 KARI 活性位点之间的有利相互作用的结果。两种先导化合物 14 和 16 的抑制常数值分别为 3.71 和 3.06µM。为了评估结合模式，对这两种化合物与 Mt KARI 的结合进行了 100ns 的分子动力学模拟，结果表明该复合物是稳定的，所有原子的平均均方根偏差小于 3.5Å。此外，化合物 16 对感染巨噬细胞模型中的 Mt 显示出最小抑制浓度为 2.06±0.91µM 和 1.9 倍对数降低的生长抑制作用。两种化合物对 RAW 264.7 细胞系的毒性较低。因此，这两种化合物都是作为抗结核药物先导物开发的有前途的候选物。
