Poopandi Saritha, Sundaraj Rajamanikandan, Rajmichael Raji, Thangaraj Sindhu, Dhamodharan Prabhu, Biswal Jayashree, Malaisamy Veerapandiyan, Jeyaraj Pandian Chitra, Jeyaraman Jeyakanthan
Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Science Block, Alagappa University, Karaikudi, 630 003, Tamil Nadu, India.
Department of Computational and Data Sciences, Indian Institute of Science, Bangalore, 560 012, Karnataka, India.
Mol Biochem Parasitol. 2021 Nov;246:111427. doi: 10.1016/j.molbiopara.2021.111427. Epub 2021 Oct 16.
Lymphatic filariasis is a parasitic disease caused by the worms Wuchereria bancrofti, Brugia malayi and Brugia timori. Three anti-filarial drugs namely Diethylcarbamazine, Ivermectin and Albendazole and their combinations are used as the control strategies for filariasis. The disease has received much attention in drug discovery due to the unavailability of vaccines and the toxic pharmaceutical properties of the existing drugs. In Wolbachia endosymbiont Brugia malayi, the UDP-N-acetylmuramoyl-tripeptide-d-alanyl-d-alanine ligase (MurF) plays a key role in peptidoglycan biosynthesis pathway and therefore can be considered as effective drug target against filariasis disease. Therefore, in the present study, MurF was selected as the therapeutic target to identify specific inhibitors against filariasis. Homology modeling was performed to predict the three-dimensional structure of MurF due to the absence of the experimental structure. Further molecular dynamics simulation and structure-based high throughput virtual screening with three different chemical databases (Zinc, Maybridge and Specs) were carried out to identify potent inhibitors and also to check their conformations inside the binding site of MurF, respectively. Top three compounds with high docking score and high relative binding affinity against MurF were selected. Further, validation studies, including predicted ADME (Absorption, Distribution, Metabolism, Excretion) assessment, binding free energy using MM-GBSA (Molecular Mechanics Generalized Born Surface Area) and DFT (Density Functional Theory) calculations were performed for the top three compounds. From the results, it was observed that all the three compounds were predicted to show high reactivity, acceptable range of pharmacokinetic properties and high binding affinity with the drug target MurF. Overall, the results could provide more understanding on the inhibition of MurF enzyme and the screened compounds could lead to the development of new specific anti-filarial drugs.
淋巴丝虫病是由班氏吴策线虫、马来布鲁线虫和帝汶布鲁线虫引起的一种寄生虫病。三种抗丝虫药物，即乙胺嗪、伊维菌素和阿苯达唑及其组合被用作丝虫病的控制策略。由于疫苗不可用以及现有药物的毒性药学特性，该疾病在药物研发中受到了广泛关注。在马来布鲁线虫的沃尔巴克氏体共生菌中，UDP-N-乙酰胞壁酰-三肽-D-丙氨酰-D-丙氨酸连接酶（MurF）在肽聚糖生物合成途径中起关键作用，因此可被视为抗丝虫病的有效药物靶点。因此，在本研究中，选择MurF作为治疗靶点来鉴定针对丝虫病的特异性抑制剂。由于缺乏实验结构，进行了同源建模以预测MurF的三维结构。进一步进行了分子动力学模拟以及使用三个不同化学数据库（Zinc、Maybridge和Specs）的基于结构的高通量虚拟筛选，分别用于鉴定强效抑制剂并检查它们在MurF结合位点内的构象。选择了对MurF具有高对接分数和高相对结合亲和力的前三种化合物。此外，对这三种化合物进行了验证研究，包括预测的ADME（吸收、分布、代谢、排泄）评估、使用MM-GBSA（分子力学广义玻恩表面积）的结合自由能和DFT（密度泛函理论）计算。从结果中可以观察到，所有这三种化合物预计都具有高反应活性、可接受的药代动力学性质范围以及与药物靶点MurF的高结合亲和力。总体而言，这些结果可以提供对MurF酶抑制作用的更多理解，并且筛选出的化合物可能会导致新型特异性抗丝虫药物的开发。
