Center for Bioinformatics, Pondicherry University, Pondicherry, India.
J Biomol Struct Dyn. 2023 Jul;41(10):4504-4514. doi: 10.1080/07391102.2022.2068073. Epub 2022 May 1.
Dengue virus is part of the flaviviruses that spread through the Aedes mosquito species and causes vascular leakage and multiple organ failure. The non-structural protein 1 (NS1) is involved in the replication of Dengue virus. The glycosylated dimeric and hexameric form of NS1 is the biologically active form. Therefore, in this study, the NS1 protein was modeled in dimeric form which is predominantly present inside the host cell. The dimeric model was validated and it was glycosylated at ASN130 and ASN207 with oligomannose. This model was simulated for 100 ns to retrieve the global minima structure. The andrographolide and its four derivatives were docked non-specifically against the dimeric glycosylated NS1 protein. The neo-andrographolide compound showed strong interactions with favorable binding energy of -8.2 kcal/mol and electrostatic binding affinity of -8.9 kcal/mol. All docked ligand-protein complexes were simulated for 100 ns. The molecular dynamics simulation analysis comprising of root mean square deviation and fluctuation, the radius of gyration, hydrogen bonding, potential energy, principal component analysis, SASA, DSSP, Free energy Landscape, MM-PBSA and Electrostatic binding affinity revealed about the stability of complex systems. These andrographolide and its derivatives was found to be interacting with Lys14 and this residue was reported as one of the important residues in NS1 activity. Among all compounds, the neo-andrographolide compound has the promising potential to inhibit the activity of the NS1 which is necessary for the Dengue virus replication.Communicated by Ramaswamy H. Sarma.
登革热病毒属于黄病毒科，通过伊蚊传播，可导致血管渗漏和多器官衰竭。非结构蛋白 1（NS1）参与登革热病毒的复制。糖基化二聚体和六聚体形式的 NS1 是具有生物活性的形式。因此，在这项研究中，以主要存在于宿主细胞内的二聚体形式对 NS1 蛋白进行建模。对二聚体模型进行了验证，并在 ASN130 和 ASN207 处糖基化形成寡甘露糖。对该模型进行了 100ns 的模拟以获取全局最小结构。将穿心莲内酯及其四种衍生物非特异性地对接至二聚体糖基化 NS1 蛋白。新穿心莲内酯化合物与该蛋白表现出强烈的相互作用，结合能为-8.2kcal/mol，静电结合亲和力为-8.9kcal/mol。所有对接的配体-蛋白复合物都进行了 100ns 的模拟。对包括均方根偏差和波动、回转半径、氢键、势能、主成分分析、溶剂可及表面积、二硫键状态分析、自由能景观、MM-PBSA 和静电结合亲和力在内的分子动力学模拟分析表明了复合物体系的稳定性。这些穿心莲内酯及其衍生物与 Lys14 相互作用，该残基被报道为 NS1 活性的重要残基之一。在所有化合物中，新穿心莲内酯化合物具有抑制 NS1 活性的潜力，这对于登革热病毒的复制是必要的。由 Ramaswamy H. Sarma 传达。
