Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening
Discovery of novel DprE1 inhibitors via computational bioactivity fingerprints and structure-based virtual screening
复制标题
通过计算生物活性指纹和基于结构的虚拟筛选发现新型 DprE1 抑制剂
DOI：
10.1038/s41401-021-00779-1
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发表时间：
2021-10-19
影响因子：
8.2
通讯作者：
Hou, Ting-jun
中科院分区：
文献类型：
--
作者：
Hu, Xue-ping;Yang, Liu;Hou, Ting-jun
十异戊二烯磷酸-β-D-核糖氧化酶（DprE 1）在分枝杆菌细胞壁的生物合成中起重要作用。DprE 1抑制剂在结核病治疗新方案的开发中显示出巨大的潜力。在这项研究中，一个集成的分子建模策略，结合计算生物活性指纹和基于结构的虚拟筛选，以确定潜在的DprE 1抑制剂。两个先导化合物（B2和H3），可以抑制DprE 1，从而在体外杀死耻垢分枝杆菌进行了鉴定。此外，化合物H3在体外显示出对结核分枝杆菌的有效抑制活性（MICMtb = 1.25 μ M）和对小鼠胚胎成纤维细胞NIH-3 T3细胞的低细胞毒性。本研究为发现新型抗结核先导化合物提供了有效的策略。
Decaprenylphosphoryl-beta-D-ribose oxidase (DprE1) plays important roles in the biosynthesis of mycobacterium cell wall. DprE1 inhibitors have shown great potentials in the development of new regimens for tuberculosis (TB) treatment. In this study, an integrated molecular modeling strategy, which combined computational bioactivity fingerprints and structure-based virtual screening, was employed to identify potential DprE1 inhibitors. Two lead compounds (B2 and H3) that could inhibit DprE1 and thus kill Mycobacterium smegmatis in vitro were identified. Moreover, compound H3 showed potent inhibitory activity against Mycobacterium tuberculosis in vitro (MICMtb = 1.25 mu M) and low cytotoxicity against mouse embryo fibroblast NIH-3T3 cells. Our research provided an effective strategy to discover novel anti-TB lead compounds.