论文标题
与ACE2的印度SARS-COV-2峰值蛋白1的建模和对接：对合并症和治疗干预的影响
Modelling and docking of Indian SARS-CoV-2 spike protein 1 with ACE2: implications for co-morbidity and therapeutic intervention
论文作者
论文摘要
目前，印度承担着非传染性疾病的最高负担，例如糖尿病（DM），高血压（HT）和心脏血管疾病（CVD），因此代表了SARS-COV-2/COVID-19 PANDEGIC的易受伤害的目标。目前，SARS-COV-2转化酶2（ACE2）对感染和发病机理的敏感性的参与是一个积极追求的研究领域。在这些情况下，在DM，HT和CVD患者中对感染的敏感性增加，而循环ACE2较高的易感性提出了与可溶性ACE2相互作用的情况，可能会导致传播的病毒感染者复合物，从而可以增强病毒的获得和病原体。因此，了解SARS-COV-2受体结合结构域-ACE2相互作用，膜结合和在细胞自由环境中都可能有助于阐明合并症在增加感染和发病机理易感性中的作用。阿奇霉素和羟基氯喹（HCQ）均显示出在受感染个体的病毒运输方面的功效。此外，这些化合物中的每一种都会产生活性代谢产物，进而可以调节病毒感受器的相互作用，从而影响临床结果。在这项研究中，我们对S1的结构相互作用与全长和可溶ACE2进行了建模。另外，将治疗药物及其活性代谢产物与可溶性ACE2蛋白进行对接。我们的结果表明，来自报告的印度序列中的任何一个S1都可以结合全长和可溶的ACE2，尽管具有不同的亲和力，这可以归因于RBD中报告的替代。此外，Azythromycin和HCQ及其活性代谢产物都可以变构影响S1与ACE2的结合。
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.
