Kabilan Shanmugampillai Jeyarajaguru, Kunjiappan Selvaraj, Sundar Krishnan, Pavadai Parasuraman, Sathishkumar Nivethitha, Velayuthaperumal Haritha
Department of Biotechnology, Kalasalingam Academy of Research and Education, Krishnankoil, 626126, Tamil Nadu, India.
Faculty of Pharmacy, Department of Pharmaceutical Chemistry, M.S. Ramaiah University of Applied Sciences, MSR Nagar, Bengaluru, 560054, Karnataka, India.
J Mol Model. 2023 Mar 6;29(4):87. doi: 10.1007/s00894-023-05488-6.
Lymphatic filariasis, generally called as elephantiasis, is a vector-borne infectious disease caused by the filarial nematodes, mainly Wuchereria bancrofti, Brugia malayi, and Brugia timori, which are transmitted through mosquitoes. The infection affects the normal flow of lymph leading to abnormal enlargement of body parts, severe pain, permanent disability, and social stigma. Due to the development of resistance as well as toxic effects, existing medicines for lymphatic filariasis are becoming ineffective in killing the adult worms. It is essential to search novel filaricidal drugs with new molecular targets. Asparaginyl-tRNA synthetase (PDB ID: 2XGT) belongs to the group of aminoacyl-tRNA synthetases that catalyze specific attachment of amino acids to their tRNA during protein biosynthesis. Plants and their extracts are well-known medicinal practice for the management of several parasitic infectious diseases including filarial infections.
In this study, asparaginyl-tRNA synthetase of Brugia malayi was used as a target to perform virtual screening of plant phytoconstituents of Vitex negundo from IMPPAT database, which exhibits anti-filarial and anti-helminthic properties. A total of sixty-eight compounds from Vitex negundo were docked against asparaginyl-tRNA synthetase using Autodock module of PyRx tool. Among the 68 compounds screened, 3 compounds, negundoside, myricetin, and nishindaside, exhibited a higher binding affinity compared to standard drugs. The pharmacokinetic and physicochemical prediction, stability of ligand-receptor complexes via molecular dynamics simulation, and density functionality theory were done further for the top-scored ligands with receptor.
淋巴丝虫病，通常称为象皮病，是一种由丝虫线虫引起的媒介传播的传染病，主要是班氏吴策线虫、马来布鲁线虫和帝汶布鲁线虫，通过蚊子传播。这种感染影响淋巴的正常流动，导致身体部位异常肿大、剧痛、永久性残疾和社会耻辱感。由于耐药性的发展以及毒性作用，现有的淋巴丝虫病药物在杀死成虫方面正变得无效。寻找具有新分子靶点的新型杀丝虫药物至关重要。天冬酰胺-tRNA合成酶（PDB编号：2XGT）属于氨酰-tRNA合成酶组，在蛋白质生物合成过程中催化氨基酸与它们的tRNA特异性结合。植物及其提取物是治疗包括丝虫感染在内的几种寄生虫传染病的著名医学实践方法。
在本研究中，以马来布鲁线虫的天冬酰胺-tRNA合成酶为靶点，对来自IMPPAT数据库的具有抗丝虫和抗蠕虫特性的黄荆植物化学成分进行虚拟筛选。使用PyRx工具的Autodock模块将总共68种来自黄荆的化合物与天冬酰胺-tRNA合成酶对接。在筛选的68种化合物中，与标准药物相比，3种化合物，即黄荆苷、杨梅素和尼辛达苷，表现出更高的结合亲和力。对得分最高的配体与受体进一步进行了药代动力学和物理化学预测、通过分子动力学模拟的配体-受体复合物稳定性以及密度泛函理论研究。
