Çubuk Hasan, Özbİl Mehmet
Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, İstanbul Arel University, İstanbul Turkey.
Institute of Biotechnology, Gebze Technical University, Kocaeli Turkey.
Turk J Chem. 2021 Feb 17;45(1):35-41. doi: 10.3906/kim-2008-35. eCollection 2021.
The new type of coronavirus, SARS-CoV-2 has affected more than 22.6 million people worldwide. Since the first day the virus was spotted in Wuhan, China, numerous drug design studies have been conducted all over the globe. Most of these studies target the receptor-binding domain of spike protein of SARS-CoV-2, which is known to bind to the human ACE2 receptor and SARS-CoV-2 main protease, vital for the virus' replication. However, there might be a third target, human furin protease, which cleaves the virus' S1-S2 domains playing an active role in its entry into the host cell. In this study, we docked five clinically used drug molecules, favipiravir, hydroxychloroquine, remdesivir, lopinavir, and ritonavir onto three target proteins, the receptor-binding domain of SARS-CoV-2 spike protein, SARS-CoV-2 main protease, and human furin protease. Results of molecular docking simulations revealed that human furin protease might be targeted by COVID-19. Remdesivir, a nucleic acid derivative, strongly bound to the active site of this protease, suggesting that this molecule can be used as a template for designing novel furin protease inhibitors to fight against the disease. Protein-drug interactions revealed in this study at the molecular level, can pave the way for better drug design for each specific target.
新型冠状病毒SARS-CoV-2已感染全球超过2260万人。自该病毒在中国武汉被发现的第一天起,全球范围内就开展了大量的药物设计研究。这些研究大多针对SARS-CoV-2刺突蛋白的受体结合结构域,该结构域已知可与人类ACE2受体和SARS-CoV-2主要蛋白酶结合,而这两种蛋白对病毒复制至关重要。然而,可能还存在第三个靶点,即人类弗林蛋白酶,它可切割病毒的S1-S2结构域,在病毒进入宿主细胞过程中发挥积极作用。在本研究中,我们将法匹拉韦、羟氯喹、瑞德西韦、洛匹那韦和利托那韦这五种临床使用的药物分子与三种靶蛋白进行对接,这三种靶蛋白分别是SARS-CoV-2刺突蛋白的受体结合结构域、SARS-CoV-2主要蛋白酶和人类弗林蛋白酶。分子对接模拟结果显示,人类弗林蛋白酶可能是COVID-19的靶点。核酸衍生物瑞德西韦与该蛋白酶的活性位点紧密结合,这表明该分子可作为设计新型弗林蛋白酶抑制剂以对抗该疾病的模板。本研究在分子水平揭示的蛋白质-药物相互作用可为针对每个特定靶点的更好药物设计铺平道路。