[论文解读] Molecular docking and binding mode analysis of selected FDA approved drugs against COVID-19 selected key protein targets: An effort towards drug repurposing to identify the combination therapy to combat COVID-19

Atanu Barik, Geeta Rai+1 more|arXiv (Cornell University)|Apr 14, 2020

SARS-CoV-2 and COVID-19 Research参考文献 17被引用 9

一句话总结

本研究通过分子对接方法，研究了四种美国食品药品监督管理局（FDA）批准的药物——氯喹、羟氯喹、瑞德西韦和阿比多尔——与SARS-CoV-2关键靶点（ACE2、RdRp/NSP12和NSP16）的结合亲和力。研究识别出参与药物-蛋白质相互作用的关键氨基酸残基，支持这些药物在COVID-19治疗中用于联合疗法的再利用潜力。

ABSTRACT

The emergence of COVID-19 has severely compromised the arsenal of antiviral and antibiotic drugs. Drug discovery is a multistep process with a high failure rate, high cost and it takes approximately 10-12 years for the development of new molecules into the clinical candidate. On the other side, drug repurposing also called old drugs for new uses, is an attractive alternative approach for a new application of marketed FDA approved or investigational drugs. In the current pandemic situation raised due to COVID-19, repurposing of existing FDA approved drugs are emerging as the first line of the treatment. The causative viral agent of this highly contagious disease and acute respiratory syndrome coronavirus (SARS-CoV) shares high nucleotide similarity. Therefore, many existing viral targets are structurally expected to be similar to SARS-CoV and likely to be inhibited by the same compounds. Here, we selected three viral key proteins based on their vital role in viral life cycle: ACE2 (helps in entry into the human host), viral nonstructural proteins RNA-dependent RNA polymerase (RdRp) NSP12, and NSP16 which helps in replication, and viral latency (invasion from immunity). The FDA approved drugs chloroquine (CQ), hydroxychloroquine (HCQ), remdesivir (RDV) and arbidol (ABD) are emerging as promising agents to combat COVID-19. Our hypothesis behind the docking studies is to determine the binding affinities of these drugs and identify the key amino acid residues playing a key role in their mechanism of action. The docking studies were carried out through Autodock and online COVID-19 docking server. Further studies on a broad range of FDA approved drugs including few more protein targets, molecular dynamics studies, in-vitro and in-vivo biological evaluation are required to identify the combination therapy targeting various stages of the viral life cycle.

研究动机与目标

• 评估FDA批准药物与关键SARS-CoV-2蛋白的结合亲和力，以加速大流行期间的药物再利用。
• 识别参与药物-蛋白质相互作用的关键氨基酸残基，以深入理解潜在抗病毒作用的机制。
• 通过靶向病毒生命周期的多个阶段，支持联合疗法的发展。
• 为后续对再利用药物的实验验证提供计算基础。
• 利用SARS-CoV与SARS-CoV-2之间的结构相似性，实现理性药物选择。

提出的方法

• 使用AutoDock和在线COVID-19分子对接服务器进行分子对接，以预测结合模式和亲和力。
• 选定三个关键病毒靶点：ACE2（病毒进入）、NSP12（RNA依赖性RNA聚合酶）和NSP16（免疫逃逸）。
• 聚焦于四种FDA批准的药物：基于其临床关注度，选择氯喹、羟氯喹、瑞德西韦和阿比多尔。
• 分析结合相互作用，以识别参与药物结合和稳定性的关键氨基酸残基。
• 采用计算方法，优先筛选出具有强结合亲和力和有利结合模式的药物。
• 提出一个未来体外和体内验证有前景药物组合的框架。

实验结果

研究问题

• RQ1 哪些FDA批准的药物对参与病毒进入和复制的关键SARS-CoV-2蛋白表现出强结合亲和力？
• RQ2 所选药物与病毒靶点之间结合相互作用中的关键氨基酸残基有哪些？
• RQ3 再利用药物在不同病毒靶点（ACE2、NSP12、NSP16）上的预测结合模式有何异同？
• RQ4 计算分子对接能否识别出靶向病毒生命周期多个阶段的联合疗法有前景的候选药物？
• RQ5 基于结构和结合分析，这些药物抑制SARS-CoV-2的潜力如何？

主要发现

• 氯喹、羟氯喹、瑞德西韦和阿比多尔对选定的SARS-CoV-2靶点表现出有利的结合亲和力，提示其具有潜在的抑制作用。
• 在ACE2、NSP12和NSP16中识别出关键氨基酸残基，这些残基对药物结合至关重要，为潜在作用机制提供了见解。
• 瑞德西韦对NSP12（RdRp）表现出强结合亲和力，支持其已知的抗RNA病毒活性。
• 阿比多尔与ACE2和NSP16均有显著结合，提示其可能在阻断病毒进入和免疫逃逸中发挥双重作用。
• 氯喹和羟氯喹与多个靶点表现出稳定的相互作用，但其结合亲和力低于瑞德西韦。
• 本研究为优先开展这些药物在联合疗法方案中的体外和体内验证提供了计算依据。