Centre for Drug Design Discovery and Development (C4D), SRM University, Delhi, Haryana, India.
Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, India.
J Biomol Struct Dyn. 2022 Mar;40(5):2189-2203. doi: 10.1080/07391102.2020.1835722. Epub 2020 Oct 19.
Tuberculosis (TB) has been recently declared as a health emergency because of sporadic increase in Multidrug-resistant Tuberculosis (MDR-TB) problem throughout the world. TB causing bacteria, has become resistant to the first line of treatment along with second line of treatment and drugs, which are accessible to us. Thus, there is an urgent need of identification of key targets and development of potential therapeutic approach(s), which can overcome the complications. In the present study, proteasome has been taken as a potential target as it is one of the key regulatory proteins in propagation. Further, a library of 400 compounds (small molecule) from Medicines for Malaria Venture (MMV) were screened against the target (proteasome) using molecular docking and simulation approach, and selected lead compounds were validated in model. In this study, we have identified two potent small molecules from the MMV Pathogen Box library, MMV019838 and MMV687146 with -9.8kcal/mol and -8.7kcal/mol binding energy respectively, which actively interact with the catalytic domain/active domain of proteasome and inhibit the growth in culture. Furthermore, the molecular docking and simulation study of MMV019838 and MMV687146 with proteasome show strong and stable interaction with compared to human proteasome and show no cytotoxicity effect. A better understanding of proteasome inhibition in in and model would eventually allow us to understand the molecular mechanism(s) and discover a novel and potent therapeutic agent against Tuberculosis. Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. Efflux pump activity was tested for a specific compound MMV019838 which was showing good in silico results than MIC values.Communicated by Ramaswamy H. Sarma.
结核病（TB）最近被宣布为一种卫生紧急情况，因为世界各地耐多药结核病（MDR-TB）问题呈零星增长。引起结核病的细菌已经对一线治疗以及我们可获得的二线治疗和药物产生了耐药性。因此，迫切需要确定关键靶标并开发潜在的治疗方法，以克服这些并发症。在本研究中，蛋白酶体被视为一个潜在的靶标，因为它是繁殖过程中的关键调节蛋白之一。此外，我们使用分子对接和模拟方法对来自疟疾药物 Venture（MMV）的 400 种化合物（小分子）文库针对目标（蛋白酶体）进行了筛选，并在模型中验证了选定的先导化合物。在这项研究中，我们从 MMV 病原体框文库中鉴定出两种有效的小分子化合物 MMV019838 和 MMV687146，它们的结合能分别为-9.8kcal/mol 和-8.7kcal/mol，它们与蛋白酶体的催化结构域/活性结构域积极相互作用，并抑制 培养物中的生长。此外，MMV019838 和 MMV687146 与蛋白酶体的分子对接和模拟研究表明，与人类蛋白酶体相比，它们与 的相互作用更强且更稳定，并且没有细胞毒性作用。更好地了解 中的蛋白酶体抑制作用和 模型最终将使我们能够理解分子机制，并发现针对结核病的新型有效治疗剂。细菌通过外排泵来对抗抗生素和化学物质的不良影响，外排泵介导的药物主动外排是产生耐药性的机制之一。对表现出良好的比 MIC 值更优的计算机模拟结果的特定化合物 MMV019838 进行了外排泵活性测试。由 Ramaswamy H. Sarma 传达。
