[论文解读] Modelling and docking of Indian SARS-CoV-2 spike protein 1 with ACE2: implications for co-morbidity and therapeutic intervention

Dhanashree D. Jagtap, Selvaa Kumar C+2 more|arXiv (Cornell University)|Apr 14, 2020

SARS-CoV-2 and COVID-19 Research参考文献 32被引用 12

一句话总结

本研究模拟了印度变异株SARS-CoV-2刺突蛋白1（S1）与膜结合型及可溶性ACE2之间的相互作用，以探讨糖尿病和高血压等共病如何增加易感性。此外，该研究将阿奇霉素和羟氯喹与可溶性ACE2对接，发现这两种药物及其活性代谢物可通过别构效应调节S1-ACE2结合，提示其可能通过减少病毒进入而发挥治疗作用的机制。

ABSTRACT

Presently, India bears amongst the highest burden of non-communicable diseases such as diabetes mellitus (DM), hypertension (HT), and cardio vascular disease (CVD) and thus represents a vulnerable target to the SARS-CoV-2/COVID-19 pandemic. Involvement of the angiotensin converting enzyme 2 (ACE2) in susceptibility to infection and pathogenesis by SARS-CoV-2 is currently an actively pursued research area. An increased susceptibility to infection in individuals with DM, HT and CVD together with higher levels of circulating ACE2 in these settings presents a scenario where interaction with soluble ACE2 may result in disseminated virus-receptor complexes that could enhance virus acquisition and pathogenesis. Thus, understanding the SARS-CoV-2 receptor binding domain-ACE2 interaction, both membrane bound and in the cell free context may contribute to elucidating the role of co-morbidities in increased susceptibility to infection and pathogenesis. Both Azithromycin and Hydroxychloroquine (HCQ) have shown efficacy in mitigating viral carriage in infected individuals. Furthermore, each of these compounds generate active metabolites which in turn may also modulate virus-receptor interaction and thus influence clinical outcomes. In this study, we model the structural interaction of S1 with both full-length and soluble ACE2. Additionally, therapeutic drugs and their active metabolites were docked with soluble ACE2 protein. Our results show that S1 from either of the reported Indian sequences can bind both full-length and soluble ACE2, albeit with varying affinity that can be attributed to a reported substitution in the RBD. Furthermore, both Azythromycin and HCQ together with their active metabolites can allosterically affect, to a range of extents, binding of S1 to ACE2.

研究动机与目标

• 理解糖尿病、高血压和心血管疾病等共病如何通过改变ACE2表达水平而增加对SARS-CoV-2感染的易感性。
• 模拟印度株SARS-CoV-2刺突蛋白S1亚基与全长ACE2及可溶性ACE2之间的结构相互作用。
• 评估阿奇霉素和羟氯喹及其活性代谢物通过别构效应调节S1-ACE2结合的潜力。
• 探讨这些相互作用对病毒致病机制及高危人群治疗干预的影响。

提出的方法

• 基于现有刺突蛋白模板，使用同源建模生成印度SARS-CoV-2变异株S1亚基的三维结构。
• 进行分子对接模拟，以预测S1与全长ACE2及可溶性ACE2之间的结合亲和力和相互作用模式。
• 将对接研究扩展至阿奇霉素、羟氯喹及其活性代谢物与可溶性ACE2的结合，以评估其别构调节潜力。
• 结构分析聚焦于S1的受体结合结构域（RBD）及ACE2中参与病毒附着的关键氨基酸残基。
• 对携带报告RBD突变与不携带该突变的S1变异株之间的结合亲和力进行了比较分析。
• 研究利用计算工具评估药物结合后结合能及构象稳定性的变化。

实验结果

研究问题

• RQ1 印度SARS-CoV-2变异株的S1亚基如何在结构水平上与膜结合型及可溶性ACE2相互作用？
• RQ2 印度SARS-CoV-2变异株中报告的RBD突变是否改变了S1与ACE2之间的结合亲和力？
• RQ3 阿奇霉素和羟氯喹及其活性代谢物能否与可溶性ACE2结合并调节S1-ACE2相互作用？
• RQ4 这些药物在多大程度上诱导ACE2发生别构变化，从而干扰病毒进入？
• RQ5 这些发现对糖尿病和高血压等共病患者有何意义？

主要发现

• 印度SARS-CoV-2变异株的S1亚基可与全长ACE2及可溶性ACE2结合，其结合亲和力受报告的RBD突变影响。
• 印度SARS-CoV-2变异株中RBD突变导致S1与ACE2之间结合能和相互作用稳定性的显著差异。
• 阿奇霉素和羟氯喹及其活性代谢物可分别结合到可溶性ACE2的特定别构位点。
• 这些药物与ACE2结合后诱导构象变化，可能干扰S1-ACE2相互作用，提示其可能通过减少病毒进入发挥治疗作用。
• 不同药物及其代谢物的别构调节程度存在差异，表明其在治疗干预中具有不同的潜力。
• 研究结果表明，共病患者体内循环ACE2水平升高可能通过促进病毒-受体复合物的稳定形成，导致病毒播散增强。