Sensing the interactions between carbohydrate-binding agents and <i>N</i>-linked glycans of SARS-CoV-2 spike glycoprotein using molecular docking and simulation studies

A recent surge in finding new candidate vaccines and potential antivirals to tackle atypical pneumonia triggered by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) needs new and unexplored approaches in solving this global pandemic. The homotrimeric transmembrane spike (S) glycoprotein of coronaviruses which facilitates virus entry into the host cells is covered with <i>N</i>-linked glycans having oligomannose and complex sugars. These glycans provide a unique opportunity for their targeting via carbohydrate-binding agents (CBAs) which have shown their antiviral potential against coronaviruses and enveloped viruses. However, CBA–ligand interaction is not fully explored in developing novel carbohydrate-binding-based antivirals due to associated unfavorable responses with CBAs. CBAs possess unique carbohydrate-binding specificity, therefore, CBAs like mannose-specific plant lectins/lectin-like mimic Pradimicin-A (PRM-A) can be used for targeting <i>N</i>-linked glycans of S glycoproteins. Here, we report studies on the binding and stability of lectins (NPA, UDA, GRFT, CV-N and wild-type and mutant BanLec) and PRM-A with the S glycoprotein glycans via docking and MD simulation. MM/GBSA calculations were also performed for docked complexes. Interestingly, stable BanLec mutant (H84T) also showed similar docking affinity and interactions as compared to wild-type BanLec, thus, confirming that uncoupling the mitogenic activity did not alter the lectin binding activity of BanLec. The stability of the docked complexes, i.e. PRM-A and lectins with SARS-CoV-2 S glycoprotein showed favorable intermolecular hydrogen-bond formation during the 100 ns MD simulation. Taking these together, our predicted <i>in silico</i> results will be helpful in the design and development of novel CBA-based antivirals for the SARS-CoV-2 neutralization. Communicated by Ramaswamy H. Sarma

针对新型严重急性呼吸综合征冠状病毒2型（severe acute respiratory syndrome coronavirus-2, SARS-CoV-2）引发的非典型肺炎，候选疫苗与潜在抗病毒药物的发掘工作迎来了迅猛增长，但应对这场全球大流行仍亟需尚未被探索的全新解决方案。冠状病毒的同源三聚体跨膜刺突（spike, S）糖蛋白介导病毒侵入宿主细胞，其表面覆盖带有寡甘露糖与复合糖结构的N-连接糖基（N-linked glycans）。这类糖基为通过糖结合剂（carbohydrate-binding agents, CBAs）实现靶向干预提供了独特契机，而CBAs已被证实对冠状病毒与包膜病毒具有抗病毒活性。然而，由于CBAs存在相关不良反应，基于糖结合的新型抗病毒药物研发中，CBA-配体相互作用的相关研究尚未得到充分探索。CBAs具备独特的糖结合特异性，因此，诸如甘露糖特异性植物凝集素/凝集素样模拟物普拉迪霉素-A（Pradimicin-A, PRM-A）这类CBAs，可用于靶向刺突糖蛋白的N-连接糖基。本研究通过分子对接与分子动力学（Molecular Dynamics, MD）模拟，分析了各类凝集素（NPA、UDA、GRFT、CV-N以及野生型与突变型BanLec）以及PRM-A与SARS-CoV-2 S糖蛋白糖基的结合特性与稳定性，并对接合复合体开展了分子力学/广义玻恩表面积（MM/GBSA）计算。值得注意的是，稳定性增强的BanLec突变体（H84T）与野生型BanLec相比，展现出相近的对接亲和力与相互作用模式，由此证实消除有丝分裂原活性并未改变BanLec的凝集素结合活性。在100纳秒（ns）的分子动力学模拟过程中，PRM-A与各类凝集素和SARS-CoV-2 S糖蛋白形成的对接复合体均表现出良好的分子间氢键形成能力，复合体稳定性优异。综合上述结果，本研究得到的计算机模拟（in silico）预测结果，将为设计与开发用于中和SARS-CoV-2的新型CBAs类抗病毒药物提供参考。本文由Ramaswamy H. Sarma转交刊发。