Department of Bioscience and Bioinformatics, Graduate School of Computer Science and Systems Engineering, Kyushu Institute of Technology, Iizuka, Japan.
Infect Disord Drug Targets. 2023;23(5):e090323214508. doi: 10.2174/1871526523666230309110705.
Tuberculosis is the second leading cause of death from infectious diseases worldwide. Multidrug-resistant Mycobacterium tuberculosis is spreading throughout the world, creating a crisis. Hence, there is a need to develop anti-tuberculosis drugs with novel structures and versatile mechanisms of action.
In this study, we identified antimicrobial compounds with a novel skeleton that inhibits mycobacterium decaprenylphosphoryl-β-D-ribose oxidase (DprE1).
A multi-step, in silico, structure-based drug screening identified potential DprE1 inhibitors from a library of 154,118 compounds. We experimentally verified the growth inhibitory effects of the eight selected candidate compounds against Mycobacterium smegmatis. Molecular dynamics simulations were performed to understand the mechanism of molecular interactions between DprE1 and ompound 4.
Eight compounds were selected through in silico screening. Compound 4 showed strong growth inhibition against M. smegmatis. Molecular dynamics simulation (50 ns) predicted direct and stable binding of Compound 4 to the active site of DprE1.
The structural analysis of the novel scaffold in Compound 4 can pave way for antituberculosis drug development and discovery.
结核病是全球第二大致死传染病。耐多药结核分枝杆菌在全球范围内传播，造成了一场危机。因此，需要开发具有新型结构和多种作用机制的抗结核药物。
在这项研究中，我们鉴定了具有抑制分枝杆菌去磷酸化 β-D-核糖基-5-磷酸二酯酶 1（DprE1）作用的新型骨架的抗菌化合物。
通过多步骤、基于结构的计算机药物筛选，从 154118 种化合物库中筛选出潜在的 DprE1 抑制剂。我们通过实验验证了这 8 种候选化合物对耻垢分枝杆菌的生长抑制作用。分子动力学模拟用于理解 DprE1 和化合物 4 之间分子相互作用的机制。
通过计算机筛选，选择了 8 种化合物。化合物 4 对耻垢分枝杆菌表现出强烈的生长抑制作用。分子动力学模拟（50 ns）预测化合物 4 可直接、稳定地与 DprE1 的活性部位结合。
对 4 号化合物中新型骨架的结构分析可以为抗结核药物的开发和发现铺平道路。
