Abstract

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, Mycobacterium tuberculosis 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 Mycobacterium tuberculosis complications. In the present study, Mycobacterium tuberculosis proteasome has been taken as a potential target as it is one of the key regulatory proteins in Mycobacterium tuberculosis 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 in vitro model. In this study, we have identified two potent small molecules from the MMV Pathogen Box library, MMV019838 and MMV687146 with −9.8 kcal/mol and −8.7 kcal/mol binding energy respectively, which actively interact with the catalytic domain/active domain of Mycobacterium tuberculosis proteasome and inhibit the Mycobacterium tuberculosis growth in in vitro culture. Furthermore, the molecular docking and simulation study of MMV019838 and MMV687146 with proteasome show strong and stable interaction with Mycobacterium tuberculosis compared to human proteasome and show no cytotoxicity effect. A better understanding of proteasome inhibition in Mycobacterium tuberculosis in in vitro and in vivo 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

摘要

由于全球耐多药结核病（MDR-TB）问题的零星增加，结核病（TB）最近被宣布为卫生紧急事件。引起结核病的细菌，结核分枝杆菌已经对一线治疗以及二线治疗和我们可以使用的药物产生抗药性。因此，迫切需要确定关键靶点并开发潜在的治疗方法，以克服结核分枝杆菌并发症。在本研究中，结核分枝杆菌蛋白酶体被认为是潜在的靶点，因为它是结核分枝杆菌的关键调控蛋白之一。传播。此外，使用分子对接和模拟方法针对目标（蛋白酶体）筛选了来自 Medicines for Malaria Venture (MMV) 的 400 种化合物（小分子）库，并在体外模型中验证了选定的先导化合物。在这项研究中，我们从 MMV Pathogen Box 文库中鉴定出两种有效的小分子 MMV019838 和 MMV687146，其结合能分别为 -9.8  kcal/mol 和 -8.7 kcal/mol，它们与结核分枝杆菌 的催化结构域/活性结构域积极相互作用蛋白酶体和体外抑制结核分枝杆菌生长文化。此外，MMV019838和MMV687146与蛋白酶体的分子对接和模拟研究表明，与人蛋白酶体相比，与结核分枝杆菌的相互作用强而稳定，并且没有细胞毒性作用。更好地了解体外和体内对结核分枝杆菌的蛋白酶体抑制作用模型最终将使我们能够了解分子机制并发现一种新型有效的结核病治疗剂。由赋予耐药性的外排泵介导的药物主动外排是细菌为对抗抗生素和化学品的不利影响而开发的机制之一。测试了特定化合物 MMV019838 的外排泵活性，该化合物的计算机结果显示优于 MIC 值。

由 Ramaswamy H. Sarma 传达