Molecular Bio-Computation & Drug Design Research Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.
Future Med Chem. 2018 Jul 1;10(14):1665-1675. doi: 10.4155/fmc-2017-0197. Epub 2018 Jun 29.
Amid the current global challenge of antimicrobial resistance, RNA polymerase remains a paramount therapeutic target for tuberculosis. Dual binding of rifampin (RIF) and a novel compound, DAAP1, demonstrated the suppression of RIF resistance. However, a paucity of data elucidating the structural mechanism of action of this synergistic interaction prevails. Methodology & results: Molecular dynamic simulations unraveled the synergistic inhibitory characteristics of DAAP1 and RIF. Co-binding induced a stable protein, increased the degree of compactness of binding site residues around RIF and subsequently an improved binding affinity toward RIF.
Findings established the structural mechanism by which DAAP1 stabilizes Mycobacterium tuberculosis RNA polymerase, thus possibly suppressing RIF resistance. This study will assist toward the design of novel inhibitors combating drug resistance in tuberculosis.
在当前全球对抗微生物药物耐药性的挑战中，RNA 聚合酶仍然是结核病的一个主要治疗靶点。利福平（RIF）和一种新型化合物 DAAP1 的双重结合证明了对 RIF 耐药性的抑制作用。然而，目前缺乏阐明这种协同相互作用的结构作用机制的数据。
分子动力学模拟揭示了 DAAP1 和 RIF 的协同抑制特性。共结合诱导了一种稳定的蛋白质，增加了 RIF 周围结合位点残基的紧凑程度，从而提高了对 RIF 的结合亲和力。
这些发现确定了 DAAP1 稳定结核分枝杆菌 RNA 聚合酶的结构机制，从而可能抑制 RIF 耐药性。本研究将有助于设计新型抑制剂来对抗结核病中的耐药性。
