School of Bio Sciences and Technology, Bioinformatics Division, Vellore Institute of Technology University, Vellore, 632014 Tamil Nadu, India.
J Mol Model. 2011 Apr;17(4):869-77. doi: 10.1007/s00894-010-0785-6. Epub 2010 Jul 1.
Remarkable advances have been made in the drug therapy of tuberculosis. However much remains to be learned about the molecular and structural basis of drug resistance in Mycobacterium tuberculosis. It is known that, activation of Isoniazid (INH) is mediated by Mycobacterium tuberculosis catalase-peroxidase (MtBKatG) and mutation at position 315 (serine to threonine) leads to resistance. We have conducted studies on the drug resistance through docking and binding analysis supported by time-scale (∼ 1000 ps) and unrestrained all-atom molecular dynamics simulations of wild and mutant MtBKatG. The study showed conformational changes of binding residues. Mutant (S315T) showed high docking score and INH binding affinity as compared to wild enzyme. In molecular dynamics simulation, mutant enzyme exhibited less structure fluctuation at INH binding residues and more degree of fluctuation at C-terminal domain compared to wild enzyme. Our computational studies and data endorse that MtBKatG mutation (S315T) decrease the flexibility of binding residues and made them rigid by altering the conformational changes, in turn it hampers the INH activity. We ascertain from this work that, this study on structural mechanism of resistance development in Mycobacterium tuberculosis would lead to new therapeutics based on the result obtained in this study.
在结核病的药物治疗方面已经取得了显著的进展。然而,关于结核分枝杆菌耐药性的分子和结构基础,仍有许多需要了解。已知异烟肼(INH)的激活是由结核分枝杆菌过氧化氢酶-过氧化物酶(MtBKatG)介导的,位置 315(丝氨酸到苏氨酸)的突变导致耐药性。我们通过对接和结合分析进行了药物耐药性研究,这些研究得到了时间尺度(约 1000 ps)和无约束全原子分子动力学模拟的支持,模拟对象是野生型和突变型 MtBKatG。研究表明了结合残基的构象变化。与野生酶相比,突变型(S315T)显示出更高的对接评分和 INH 结合亲和力。在分子动力学模拟中,与野生酶相比,突变酶在 INH 结合残基处的结构波动较小,在 C 末端结构域的波动较大。我们的计算研究和数据表明,MtBKatG 突变(S315T)通过改变构象变化降低了结合残基的灵活性,使它们变得僵硬,从而抑制了 INH 的活性。我们从这项工作中确定,对结核分枝杆菌耐药性发展的结构机制的研究将基于本研究的结果产生新的治疗方法。