Mathew Shilu, Taleb Sara, Eid Ali Hussein, Althani Asmaa A, Yassine Hadi M
Biomedical Research Center, Qatar University, Doha, 2713 Qatar.
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
Emergent Mater. 2022;5(2):295-305. doi: 10.1007/s42247-021-00213-6. Epub 2021 May 3.
Human respiratory syncytial virus (RSV) is a leading ubiquitous respiratory pathogen in newborn infants, young children, and the elderly, with no vaccine available to date. The viral fusion glycoprotein (RSV F) plays an essential role in the infection process, and it is a primary target of neutralizing antibodies, making it an attractive site for vaccine development. With this in view, there is a persistent need to identify selective antiviral drugs against RSV, targeting the major antigenic sites on the F protein. We aimed to conduct a robust in silico high-throughput drug screening of one million compounds to explore potential inhibitors that bind the major antigenic site Ø and site II on RSV F protein, which are the main target of neutralizing antibodies (NAb). We utilized the three-dimensional crystallographic structure of both antigenic site Ø on pre-F and antigenic II on post-F to screen for potential anti-RSV inhibitors. A library of one million small compounds was docked to explore lead binders in the major antigenic sites by using virtual lab bench CLC Drug Discovery. We also performed Quantitative Structure-Activity and Relationship (QSAR) for the lead best binders known for their antiviral activity. Among one million tested ligands, seven ligands (PubChem ID: 3714418, 24787350, 49828911, 24802036, 79824892, 49726463, and 3139884) were identified as the best binders to neutralizing epitopes site Ø and four ligands (PubChem ID: 865999, 17505357, 24802036, and 24285058) to neutralizing epitopes site II, respectively. These binders exhibited significant interactions with neutralizing epitopes on RSV F, with an average of six H bonds, docking energy of - 15.43 Kcal·mol, and minimum interaction energy of - 7.45 Kcal·mol. Using in silico virtual screening, we identified potential RSV inhibitors that bind two major antigenic sites on the RSV F protein. Using structure-based design and combination-based drug therapy, identified molecules could be modified to generate the next generation anti-RSV drugs.
The online version contains supplementary material available at 10.1007/s42247-021-00213-6.
人呼吸道合胞病毒（RSV）是新生儿、幼儿和老年人中普遍存在的主要呼吸道病原体，迄今为止尚无可用疫苗。病毒融合糖蛋白（RSV F）在感染过程中起关键作用，并且是中和抗体的主要靶标，使其成为疫苗开发的一个有吸引力的位点。有鉴于此，一直需要鉴定针对RSV的选择性抗病毒药物，靶向F蛋白上的主要抗原位点。我们旨在对100万种化合物进行强大的计算机高通量药物筛选，以探索结合RSV F蛋白上主要抗原位点Ø和位点II的潜在抑制剂，这两个位点是中和抗体（NAb）的主要靶标。我们利用前体F上的抗原位点Ø和后体F上的抗原位点II的三维晶体结构来筛选潜在的抗RSV抑制剂。通过使用虚拟实验室工作台CLC药物发现工具，对接一个包含100万种小分子化合物的文库，以探索主要抗原位点中的潜在结合剂。我们还对已知具有抗病毒活性的最佳先导结合剂进行了定量构效关系（QSAR）研究。在100万个测试配体中，分别鉴定出7种配体（PubChem ID：3714418、24787350、49828911、24802036、79824892、49726463和3139884）为中和表位位点Ø的最佳结合剂，4种配体（PubChem ID：865999、17505357、24802036和24285058）为中和表位位点II的最佳结合剂。这些结合剂与RSV F上的中和表位表现出显著相互作用，平均有6个氢键，对接能为 - 15.43千卡·摩尔，最小相互作用能为 - 7.45千卡·摩尔。通过计算机虚拟筛选，我们鉴定出了结合RSV F蛋白上两个主要抗原位点的潜在RSV抑制剂。利用基于结构的设计和基于组合的药物疗法，可对鉴定出的分子进行修饰以生成下一代抗RSV药物。
在线版本包含可在10.1007/s42247-021-00213-6获取的补充材料。
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