Identification of potent inhibitors of COVID-19 main protease by using In Silico methods

COVID-19 pandemic caused by a newly emerged coronavirus. This severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) outbreak poses a serious public health risk. Also the global health concerns raised, because this viral infection spreads from person to person in some case with no reported symptoms. This pandemic situation encourages drug repurposing of the available drugs such as hydroxychloroquine and remdesivir for the COVID-19 treatment. Drug repurposing could improve the existing clinical management. Current study, aims to predict the viral protease inhibitor for the COVID-19 main protease (M^pro). This COVID-19 M^pro enzyme cuts the polyproteins translated from viral RNA to yield functional viral proteins. The crystal structure of M^pro (PDB ID: 6LU7) was obtained from Protein Data bank. Molecular docking investigations between the target protein and ligands were performed using PyRx virtual Screening software. All the test compounds got docked with the targeted viral protein. Present <i>in silico</i> study suggest Notomycin, Coumermycin A1, and Suramin as potent M^proinhibitor based on the binding energy and molecular interactions. However, further research is necessary to investigate their potential therapeutic use. All relevant molecular docking data and supporting information is accessible freely from the www.findrug.org. <br> Virtual Screening PyRx is a Virtual Screening software for computational drug discovery that can be used to screen libraries of compounds against potential drug targets. Virtual molecular screening is used to dock small-molecule libraries to a macromolecule in order to find lead compounds with desired biological function. This in silico method is well known for its application in computer-aided drug design. PyRx is open-source software with an intuitive user interface that runs on all major computer operating systems.<br>AcknowledgementVIT-SIF Lab, SAS, Chemistry Division for NMR and GC-MS Analysis.<br> <br>

由新型冠状病毒引发的COVID-19（新型冠状病毒肺炎）疫情，其病原体为严重急性呼吸综合征冠状病毒2型（SARS-CoV-2），此次暴发对公共卫生构成严重威胁。该病毒可在无显性症状的情况下实现人际传播，由此引发了全球范围内的健康关切。此次疫情推动了针对COVID-19治疗的现有药物再利用研究，例如羟氯喹与瑞德西韦。药物再利用可优化现有临床诊疗方案。
本研究旨在筛选可靶向COVID-19主要蛋白酶（M^pro）的病毒蛋白酶抑制剂。COVID-19的M^pro酶可切割由病毒RNA翻译得到的多聚蛋白，进而生成具有功能活性的病毒蛋白。M^pro的晶体结构（PDB编号：6LU7）取自蛋白质数据银行（Protein Data Bank，PDB）。
本研究采用PyRx虚拟筛选软件，开展靶蛋白与配体间的分子对接研究，所有受试化合物均与该靶标病毒蛋白完成了分子对接。本次计算机模拟（in silico）研究结果显示，基于结合能与分子相互作用分析，诺妥霉素（Notomycin）、库霉素A1（Coumermycin A1）与苏拉明（Suramin）可作为强效M^pro抑制剂。不过，仍需开展进一步研究以验证其潜在的临床治疗应用价值。所有相关分子对接数据与辅助信息均可从www.findrug.org免费获取。
PyRx虚拟筛选软件是一款用于计算药物发现的虚拟筛选工具，可针对潜在药物靶标筛选化合物文库。虚拟分子筛选通过将小分子化合物文库与大分子进行分子对接，以筛选出具备预期生物学功能的先导化合物。该计算机模拟方法在计算机辅助药物设计领域应用广泛。PyRx为开源软件，具备直观的用户界面，可兼容所有主流计算机操作系统。
致谢：感谢VIT-SIF实验室、SAS与化学分部为核磁共振（Nuclear Magnetic Resonance, NMR）及气相色谱-质谱联用（Gas Chromatography-Mass Spectrometry, GC-MS）分析提供的支持。