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.