Department of Biomedical Science, Acharya Narendra Dev College, University of Delhi, New Delhi, India.
Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology (CSIR-IGIB), New Delhi, India.
SLAS Discov. 2020 Jan;25(1):70-78. doi: 10.1177/2472555219881148. Epub 2019 Oct 9.
The rapid rise in the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of (Mtb) mandates the discovery of novel tuberculosis (TB) drugs. Mur enzymes, which are identified as essential proteins in Mtb and catalyze the cytoplasmic steps in the peptidoglycan biosynthetic pathway, are considered potential drug targets. However, none of the clinical drugs have yet been developed against these enzymes. Hence, the aim of this study was to identify novel inhibitors of Mur enzymes in . We screened an antitubercular compound library of 684 compounds, using MurB and MurE enzymes of the Mtb Mur pathway as drug targets. For experimental validation, the top hits obtained on in silico screening were screened in vitro, using Mtb Mur enzyme-specific assays. In all, seven compounds were found to show greater than 50% inhibition, with the highest inhibition observed at 77%, and the IC for these compounds was found to be in the range of 28-50 μM. Compound 5175112 showed the lowest IC (28.69 ± 1.17 μM), and on the basis of (1) the binding affinity, (2) the stability of interaction noted on molecular dynamics simulation, and (3) an in vitro assay, MurE appeared to be its target enzyme. We believe that the overall strategy followed in this study and the results obtained are a good starting point for developing Mur enzyme-specific Mtb inhibitors.
（结核分枝杆菌）中多药耐药（MDR）和广泛耐药（XDR）菌株的迅速出现，要求发现新的结核病（TB）药物。Mur 酶被确定为结核分枝杆菌中的必需蛋白，催化肽聚糖生物合成途径中的细胞质步骤，被认为是潜在的药物靶点。然而，目前还没有针对这些酶的临床药物。因此，本研究的目的是在 中鉴定 Mur 酶的新型抑制剂。我们以结核分枝杆菌 Mur 途径的 MurB 和 MurE 酶为药物靶点，筛选了 684 种化合物的抗结核化合物库。为了进行实验验证，我们在体外筛选了基于计算机筛选获得的前几个命中化合物，使用结核分枝杆菌 Mur 酶特异性测定法进行筛选。总之，发现有七种化合物的抑制率超过 50%，最高抑制率为 77%，这些化合物的 IC 值在 28-50 μM 范围内。化合物 5175112 的 IC 值最低（28.69 ± 1.17 μM），根据（1）结合亲和力、（2）分子动力学模拟中观察到的相互作用稳定性，以及（3）体外测定，MurE 似乎是其靶酶。我们相信，本研究中采用的总体策略和获得的结果为开发 Mur 酶特异性结核分枝杆菌抑制剂提供了一个良好的起点。
