Liang Hualou, Zhao Liang, Gong Xiajing, Hu Meng, Wang Hongbin
School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
Clin Transl Sci. 2021 May;14(3):1123-1132. doi: 10.1111/cts.13007. Epub 2021 May 2.
The outbreak of the novel coronavirus severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) respiratory disease, led to a global pandemic with high morbidity and mortality. Despite frenzied efforts in therapeutic development, there are currently no effective drugs for treatment, nor are there vaccines for its prevention. Drug repurposing, representing as an effective drug discovery strategy from existing drugs, is one of the most practical treatment options against the outbreak. In this study, we present a novel strategy for in silico molecular modeling screening for potential drugs that may interact with multiple main proteins of SARS-CoV-2. Targeting multiple viral proteins is a novel drug discovery concept in that it enables the potential drugs to act on different stages of the virus' life cycle, thereby potentially maximizing the drug potency. We screened 2631 US Food and Drug Administration (FDA)-approved small molecules against 4 key proteins of SARS-CoV-2 that are known as attractive targets for antiviral drug development. In total, we identified 29 drugs that could actively interact with 2 or more target proteins, with 5 drugs (avapritinib, bictegravir, ziprasidone, capmatinib, and pexidartinib) being common candidates for all 4 key host proteins and 3 of them possessing the desirable molecular properties. By overlaying docked positions of drug candidates onto individual host proteins, it has been further confirmed that the binding site conformations are conserved. The drugs identified in our screening provide potential guidance for experimental confirmation, such as in vitro molecular assays and in vivo animal testing, as well as incorporation into ongoing clinical studies.
新型冠状病毒严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是2019冠状病毒病（COVID-19）呼吸道疾病的病原体，其爆发导致了一场具有高发病率和死亡率的全球大流行。尽管在治疗药物研发方面付出了巨大努力，但目前尚无有效的治疗药物，也没有预防疫苗。药物重新利用作为一种从现有药物中发现有效药物的策略，是应对此次疫情最切实可行的治疗选择之一。在本研究中，我们提出了一种新的策略，通过计算机模拟分子建模来筛选可能与SARS-CoV-2多种主要蛋白相互作用的潜在药物。针对多种病毒蛋白是一种新的药物发现概念，因为它能使潜在药物作用于病毒生命周期的不同阶段，从而有可能使药物效力最大化。我们针对SARS-CoV-2的4种关键蛋白筛选了2631种美国食品药品监督管理局（FDA）批准的小分子，这些蛋白是抗病毒药物研发的有吸引力的靶点。我们总共鉴定出29种能与2种或更多靶点蛋白发生积极相互作用的药物，其中5种药物（阿伐替尼、比克替拉韦、齐拉西酮、卡马替尼和培西达替尼）是所有4种关键宿主蛋白的共同候选药物，且其中3种具有理想的分子特性。通过将候选药物的对接位置叠加到各个宿主蛋白上，进一步证实了结合位点构象是保守的。我们筛选出的这些药物为实验验证提供了潜在指导，如体外分子试验和体内动物试验，以及纳入正在进行的临床研究。
