Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein.
Supervised molecular dynamics for exploring the druggability of the SARS-CoV-2 spike protein.
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探索SARS-CoV-2刺突蛋白药物性的监督分子动力学。
DOI：
10.1007/s10822-020-00356-4
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发表时间：
2021-03
影响因子：
3.5
通讯作者：
Reynolds CA
中科院分区：
文献类型：
--
作者：
Deganutti G;Prischi F;Reynolds CA
最近爆发的与呼吸综合征相关的冠状病毒(SARS-CoV-2)正在刺激一场史无前例的科学运动，以减轻冠状病毒病(新冠肺炎)的负担。一系列研究集中在通过改变批准用于其他疾病的药物的用途来瞄准对其复制至关重要的SARS-CoV-2蛋白质。病毒与宿主细胞之间的第一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Spike蛋白的受体结合域(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，我们在Silico中筛选了2421个批准的小分子，并通过广泛的分子动力学模拟验证了对接结果。在6种可能与RBD结合的药物中，进一步评估了头孢菌素抗生素头孢素A对RBD和ACE2结合的影响，这表明在判断任何潜在的候选药物时，考虑RBD和ACE2之间的异源二聚体的动态形成是重要的。本文的在线版本(10.1007/s10822-020-00356-4)包含向授权用户提供的补充材料。
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. The online version of this article (10.1007/s10822-020-00356-4) contains supplementary material, which is available to authorized users.
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影响因子：
5.6
作者：
Deganutti, Giuseppe;Moro, Stefano;Reynolds, Christopher A.
通讯作者：
Reynolds, Christopher A.
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
3.7
作者：
COLLINS, AR;KNOBLER, RL;BUCHMEIER, MJ
通讯作者：
BUCHMEIER, MJ
影响因子：
20.1
作者：
Donoghue, M;Hsieh, F;Acton, S
通讯作者：
Acton, S
影响因子：
4.9
作者：
Dyall, Julie;Coleman, Christopher M.;Frieman, Matthew B.
通讯作者：
Frieman, Matthew B.