Introduction
For the past three decades, the outbreak of new viruses causing strange epidemic diseases and high mortality. Among these viruses, notably, Influenza, Hepatitis, and HIV viruses are high replicative in nature and no drugs available to stop the infection and give a complete cure. Coronavirus is a RNA virus which was emerged and evolved to different types of coronaviruses.[1,2] Among these, the outbreak of the SARS-CoV virus in 2002 made a major health threat to the public and caused Severe Acute Respiratory Syndrome (SARS), it resulted in 774 deaths over the 8098 infected cases.[3,4]The evolution of coronavirus was continuous, in the year 2012, another version of Middle East Respiratory Syndrome-CoV (MERS-CoV) virus also emerged, which is found to be vulnerable and the outbreak of the MERS-CoV virus made high health emergency in the Middle East countries, infected 2506 people and resulted in 862 deaths.[5,6] Further, recently, a new type of coronavirus also again emerged in Wuhan, China in December, 2019, which was identified as a novel coronavirus SARS-CoV-2 namely COVID-19, which causes severe acute respiratory infection (pneumonia) and other health problems.[7-9] As on date, nearly 4 million people were infected, in which 2,84,034 people died. Such high mortality rate may be due to several reasons, however, it is widely accepted that the mode of infection of SARS-CoV-2 is different from the SARS-CoV and MERS-CoV. As per reports SARS-CoV-2 is a beta coronavirus, its genome sequence is 79% identical to SARS-CoV and 50% identical to MERS-CoV.[10] SARS-CoV-2 is an enveloped single positive-stranded RNA virus. The viral structure consists of structural proteins such as spike (S), membrane (M), envelope (E) and nucleocapsid (N). The spike S-protein presents in the envelope of the virus mediates the viral particle into the host-cells. M-protein is largely present in the virion and jointly with E-protein forms a mature viral envelope. N-protein always binds with RNA, which is required for the packing of viral RNA.[11,12] SARS-CoV-2 initiates human cell entry after the spike (S) protein present on the envelope binds to a cell membrane receptor called the angiotensin converting enzyme (ACE2). The S-protein is cleaved into two subunits S1 and S2, by a human cell-derived protease (thought to be Furin), subsequently, S1 binds to its receptor, ACE2. The other fragment, S2, is cleaved by TMPRSS2 (Transmembrane protease serine 2), a human cell surface serine protease, resulting in membrane fusion. Both ACE2 and TMPRSS2 are therefore thought to be essential in airway cells for SARS-CoV-2 infection. Inhibiting TMPRSS2 protein using suitable inhibitors can stop the virus entry and this prevents the SARS-CoV-2 virus infection. The present study is focused to find the inhibitors of TMPRSS2 protein from the existing drugs.[13-17] Camostat mesylate, nafamostat, and leupeptin (Figure 1) are the drugs chosen as the inhibitors of TMPRSS2. Among these, camostat and nafamostat are already been in clinical trials and using for COVID-19[13,16,18-21], and Leupeptin[22] also tested for SARS-CoV-2 virus infection. To understand the molecular mechanism of binding of these molecules is not completely known at molecular dynamics level; hence, we have computed the binding affinity, intermolecular interactions, and stability of molecules from the molecular docking and the molecular dynamics simulations. The information obtained from this computational study is useful to consider these drugs as a repurposed drug for the therapeutic agents of COVID-19, however it is subjected to clinical studies and other requirements.