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Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein
Journal of Computer-Aided Molecular Design ( IF 3.5 ) Pub Date : 2020-10-26 , DOI: 10.1007/s10822-020-00356-4
Giuseppe Deganutti , Filippo Prischi , Christopher A. Reynolds

The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs approved for other diseases. The first interaction between the virus and the host cell is mediated by the spike protein on the virus surface and the human angiotensin-converting enzyme (ACE2). Small molecules able to bind the receptor-binding domain (RBD) of the spike protein and disrupt the binding to ACE2 would offer an important tool for slowing, or even preventing, the infection. Here, we screened 2421 approved small molecules in silico and validated the docking outcomes through extensive molecular dynamics simulations. Out of six drugs characterized as putative RBD binders, the cephalosporin antibiotic cefsulodin was further assessed for its effect on the binding between the RBD and ACE2, suggesting that it is important to consider the dynamic formation of the heterodimer between RBD and ACE2 when judging any potential candidate.



中文翻译:

有监督的分子动力学,以探索SARS-CoV-2穗突蛋白的药物作用

最近爆​​发的与呼吸综合征相关的冠状病毒(SARS-CoV-2)引发了前所未有的科学运动,以减轻冠状病毒疾病(COVID-19)的负担。一项研究重点是通过重新利用批准用于其他疾病的药物,针对SARS-CoV-2蛋白的复制基础。病毒与宿主细胞之间的首次相互作用是由病毒表面的刺突蛋白和人类血管紧张素转换酶(ACE2)介导的。能够结合刺突蛋白的受体结合结构域(RBD)并破坏与ACE2的结合的小分子将为减缓甚至预防感染提供重要的工具。在这里,我们筛选了2421个核准的小分子silico,并通过广泛的分子动力学模拟验证了对接结果。在六种被认为是RBD结合剂的药物中,进一步评估了头孢菌素头孢磺啶对RBD和ACE2之间结合的影响,这表明,在判断任何潜在的可能性时,考虑RBD和ACE2之间异源二聚体的动态形成非常重要。候选人。

更新日期:2020-10-26
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