Coronaviruses are enveloped positive-strand RNA viruses belonging to family Coronaviridae and order Nidovirales which cause infections in birds and mammals. Among the human coronaviruses, highly pathogenic ones are Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome coronavirus (MERS-CoV) which have been implicated in severe respiratory syndrome in humans. There are no approved antiviral drugs or vaccines for the treatment of human CoV infection to date. The recent outbreak of new coronavirus pandemic, coronavirus disease 2019 (COVID-19) has caused a high mortality rate and infections around the world which necessitates the need for the discovery of novel anti-coronaviral drugs. Among the coronaviruses proteins, 3C-like protease (3CL^pro) is an important drug target against coronaviral infection as the auto-cleavage process catalysed by the enzyme is crucial for viral maturation and replication. The present work is aimed at the identification of suitable lead molecules for the inhibition of 3CL^pro enzyme via a computational screening of the Food and Drug Administration (FDA) approved antiviral drugs and phytochemicals. Based on binding energies and molecular interaction studies, we shortlisted five lead molecules (both FDA approved drugs and phytochemicals) for each enzyme targets (SARS-CoV-2 3CL^pro, SARS-CoV 3CL^pro and MERS-CoV 3CL^pro). The lead molecules showed higher binding affinity compared to the standard inhibitors and exhibited favourable hydrophobic interactions and a good number of hydrogen bonds with their respective targets. A few promising leads with dual inhibition potential were identified among FDA approved antiviral drugs which include DB13879 (Glecaprevir), DB09102 (Daclatasvir), molecule DB09297 (Paritaprevir) and DB01072 (Atazanavir). Among the phytochemicals, 11,646,359 (Vincapusine), 120,716 (Alloyohimbine) and 10,308,017 (Gummadiol) showed triple inhibition potential against all the three targets and 102,004,710 (18-Hydroxy-3-epi-alpha-yohimbine) exhibited dual inhibition potential. Hence, the proposed lead molecules from our findings can be further investigated through in vitro and in vivo studies to develop into potential drug candidates against human coronaviral infections.

冠状病毒是有包膜的正链 RNA 病毒，属于冠状病毒科和嵌套病毒目，可导致鸟类和哺乳动物感染。在人类冠状病毒中，高致病性的是严重急性呼吸系统综合症冠状病毒（SARS-CoV）和中东呼吸系统综合症冠状病毒（MERS-CoV），它们与人类的严重呼吸系统综合症有关。迄今为止，尚无批准用于治疗人类冠状病毒感染的抗病毒药物或疫苗。最近爆​​发的新型冠状病毒大流行，冠状病毒病 2019 (COVID-19) 在世界范围内造成了高死亡率和高感染率，因此需要发现新型抗冠状病毒药物。在冠状病毒蛋白中，类 3C 蛋白酶（3CL^pro ) 是抗冠状病毒感染的重要药物靶标，因为酶催化的自动切割过程对于病毒成熟和复制至关重要。目前的工作旨在通过食品和药物管理局 (FDA) 批准的抗病毒药物和植物化学物质的计算筛选，鉴定用于抑制 3CL^{酶原的合适先导分子。基于结合能和分子相互作用研究，我们为每个酶靶点（SARS-CoV-2 3CL pro}、SARS-CoV 3CL ^pro和 MERS-CoV 3CL ^pro）筛选出五个先导分子（FDA 批准的药物和植物化学物质）). 与标准抑制剂相比，先导分子显示出更高的结合亲和力，并表现出有利的疏水相互作用和与其各自目标的大量氢键。在 FDA 批准的抗病毒药物中发现了一些具有双重抑制潜力的有前途的线索，包括 DB13879 (Glecaprevir)、DB09102 (Daclatasvir)、分子 DB09297 (Paritaprevir) 和 DB01072 (Atazanavir)。在植物化学物质中，11,646,359（长春花碱）、120,716（Alloyohimbine）和 10,308,017（Gummadiol）对所有三个靶标均显示出三重抑制潜力，而 102,004,710（18-Hydroxy-3-epi-alpha-yohimbine）则表现出双重抑制潜力。因此，可以通过体外和体内进一步研究我们研究结果中提出的先导分子研究以开发针对人类冠状病毒感染的潜在候选药物。