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submitted on 21.04.2020, 16:06 and posted on 22.04.2020, 12:42by Kailas Sonawane, Sagar S. Barale, Maruti J. Dhanavade, Shailesh R. Waghmare, Naiem H. Nadaf, Subodh A. Kamble, Ali Abdulmawjood Mohammed, Asiya M. Makandar, Prayagraj M. Fandilolu, Ambika S. Dound, Nitin M. Naik
rapid outbreak of SARS-Coronavirus 2 (SARS-CoV-2) caused a serious global
public health threat. The spike ‘S’ protein of SARS-CoV-2 and ACE2 of the host
cell are being targeted to design and discover new drugs to control Covid-19
disease. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell
has been found to play a significant role in proteolytic cleavage of viral
spike protein priming to the receptor ACE2 present in human cell. However,
three dimensional structure and inhibition mechanism of TMPRSS2 is yet to be explored
experimentally. Hence, in the present study we have generated a homology model
of TMPRSS2 and studied its binding properties with experimentally studied
inhibitors viz. Camostat mesylate, Nafamostat and Bromhexine
hydrochloride (BHH) using molecular docking technique. Docking analysis
revealed that the Camostat mesylate and its structural analogue Nafamostat
interacts strongly with residues His296, Ser441 and Asp435 present in catalytic
triad of TMPRSS2. However, BHH interacts with Gln438 and other residues present
in the active site pocket of TMPRSS2 through hydrophobic contacts effectively.
Thus, these results revealed the inhibition mechanism of TMPRSS2 by known
inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride in detail
at the molecular level. However, Camostat mesylate shows strong binding as
compared to other two inhibitors. This structural information could also be
useful to design and discover new inhibitors of TMPRSS2, which may be helpful
to prevent the entry to SARS-Coronavirus 2 in human cell.