2 research outputs found
Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2
The
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
Structural insights and inhibition mechanism of TMPRSS2 by experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride to control SARS-coronavirus-2: A molecular modeling approach
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has been responsible for the cause of global pandemic Covid-19 and to date, there is no effective treatment available. The spike ‘S’ protein of SARS-CoV-2 and ACE2 of the host cell are being targeted to design new drugs to control Covid-19. Similarly, a transmembrane serine protease, TMPRSS2 of the host cell plays a significant role in the proteolytic cleavage of viral ‘S’ protein helpful for the priming of ACE2 receptors and viral entry into human cells. However, three-dimensional structural information and the inhibition mechanism of TMPRSS2 is yet to be explored experimentally. Hence, we have used a molecular dynamics (MD) simulated homology model of TMPRSS2 to study the inhibition mechanism of experimentally known inhibitors Camostat mesylate, Nafamostat and Bromhexine hydrochloride (BHH) using molecular modeling techniques. Prior to docking, all three inhibitors were geometry optimized by semi-empirical quantum chemical RM1 method. Molecular docking analysis revealed that Camostat mesylate and its structural analogue Nafamostat interact strongly with residues His296 and Ser441 present in the catalytic triad of TMPRSS2, whereas BHH binds with Ala386 along with other residues. Comparative molecular dynamics simulations revealed the stable behavior of all the docked complexes. MM-PBSA calculations also revealed the stronger binding of Camostat mesylate to TMPRSS2 active site residues as compared to Nafamostat and BHH. Thus, this structural information could be useful to understand the mechanistic approach of TMPRSS2 inhibition, which may be helpful to design new lead compounds to prevent the entry of SARS-Coronavirus 2 in human cells