一种综合药物再利用策略,用于快速鉴定潜在的 SARS-CoV-2 病毒抑制剂。

An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors.

机构信息

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100, Siena, Italy.

School of Life Sciences, University of Essex, Colchester, CO4 3SQ, UK.

出版信息

Sci Rep. 2020 Aug 17;10(1):13866. doi: 10.1038/s41598-020-70863-9.

Abstract

The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.

摘要

新型冠状病毒病(COVID-19)是由严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)引起的传染病。该病毒在人类中迅速传播,导致持续的冠状病毒大流行。最近的研究表明,与 SARS-CoV 类似,SARS-CoV-2 使用包膜上的刺突糖蛋白来识别和结合人类受体 ACE2。这一事件启动了病毒和宿主细胞膜的融合,然后病毒进入宿主细胞。尽管正在进行多项临床研究,但目前尚无专门针对 SARS-CoV-2 的批准疫苗或药物。在有效的疫苗问世之前,重新利用已获 FDA 批准的药物与从头发现药物相比,可以显著缩短时间并降低成本。在这项研究中,我们试图通过应用强大的药物再利用策略来克服计算机虚拟筛选的局限性。我们将对接模拟与分子动力学(MD)、有监督的 MD(SuMD)和引导 MD(SMD)模拟相结合,以鉴定刺突蛋白 - ACE2 相互作用抑制剂。我们的数据表明,西美瑞韦和卢美他韦与刺突蛋白的受体结合域具有高亲和力,并阻止 ACE2 相互作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4637/7431416/b17b592e718d/41598_2020_70863_Fig1_HTML.jpg

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