Dengue infection is the most common arthropod‐borne disease caused by dengue viruses, predominantly affecting millions of human beings annually. To find out promising chemical entities for therapeutic application in Dengue, in the current research, a multi‐step virtual screening effort was conceived to screen out the entire “screening library” of the Asinex database. Initially, through “Lipinski rule of five” filtration criterion almost 0.6 million compounds were collected and docked with NS3‐NS2B protein. Thereby, the chemical space was reduced to about 3500 compounds through the analysis of binding affinity obtained from molecular docking study in AutoDock Vina. Further, the “Virtual Screening Workflow” (VSW) utility of Schrödinger suite was used, which follows a stepwise multiple docking programs such as ‐ high‐throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking, and in postprocessing analysis the MM‐GBSA based free binding energy calculation. Finally, five potent molecules were proposed as potential inhibitors for the dengue NS3‐NS2B protein based on the investigation of molecular interactions map and protein‐ligand fingerprint analyses. Different pharmacokinetics and drug‐likeness parameters were also checked, which favour the potentiality of selected molecules for being drug‐like candidates. The molecular dynamics (MD) simulation analyses of protein‐ligand complexes were explained that NS3‐NS2B bound with proposed molecules quite stable in dynamic states as observed from the root means square deviation (RMSD) and root means square fluctuation (RMSF) parameters. The binding free energy was calculated using MM‐GBSA method from the MD simulation trajectories revealed that all proposed molecules possess such a strong binding affinity towards the dengue NS3‐NS2B protein. Therefore, proposed molecules may be potential chemical components for effective inhibition of dengue NS3‐NS2B protein subjected to experimental validation.

中文翻译：

---

化学数据库的结构引导筛选，以识别 NS3-NS2B 抑制剂，以有效治疗登革热感染。

登革热感染是由登革热病毒引起的最常见的节肢动物传播疾病，每年主要影响数百万人。为了找出用于登革热治疗应用的有前景的化学实体，在当前的研究中，设想了多步虚拟筛选工作来筛选 Asinex 数据库的整个“筛选库”。最初，通过“Lipinski 5 法则”过滤标准，收集了近 60 万个化合物并与 NS3-NS2B 蛋白对接。因此，通过分析 AutoDock Vina 中分子对接研究获得的结合亲和力，化学空间减少到约 3500 个化合物。此外，使用了薛定谔套件的“虚拟筛选工作流程”（VSW）实用程序，它遵循逐步的多对接程序，例如高通量虚拟筛选 (HTVS)、标准精密 (SP) 和超精密 (XP) 对接，并在后处理分析中基于 MM-GBSA 的自由结合能计算。最后，基于分子相互作用图谱和蛋白质-配体指纹分析的研究，提出了五种有效分子作为登革热 NS3-NS2B 蛋白的潜在抑制剂。还检查了不同的药代动力学和药物相似性参数，这有利于所选分子成为药物样候选物的潜力。蛋白质-配体复合物的分子动力学 (MD) 模拟分析解释了 NS3-NS2B 与提议的分子结合在动态状态下非常稳定，如从均方根偏差 (RMSD) 和均方根波动 (RMSF) 参数观察到的。结合自由能使用 MM-GBSA 方法从 MD 模拟轨迹计算表明，所有提出的分子都对登革热 NS3-NS2B 蛋白具有如此强的结合亲和力。因此，所提出的分子可能是有效抑制登革热 NS3-NS2B 蛋白的潜在化学成分，经过实验验证。结合自由能使用 MM-GBSA 方法从 MD 模拟轨迹计算表明，所有提出的分子都对登革热 NS3-NS2B 蛋白具有如此强的结合亲和力。因此，所提出的分子可能是有效抑制登革热 NS3-NS2B 蛋白的潜在化学成分，经过实验验证。结合自由能使用 MM-GBSA 方法从 MD 模拟轨迹计算表明，所有提出的分子都对登革热 NS3-NS2B 蛋白具有如此强的结合亲和力。因此，所提出的分子可能是有效抑制登革热 NS3-NS2B 蛋白的潜在化学成分，经过实验验证。