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Homology Modeling and Docking Studies of TMPRSS2 with Experimentally Known Inhibitors Camostat Mesylate, Nafamostat and Bromhexine Hydrochloride to Control SARS-Coronavirus-2

preprint
submitted on 21.04.2020, 16:06 and posted on 22.04.2020, 12:42 by 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
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.

Funding

DST-SERB, New Delhi for financial support (Ref. No. EMR/2017/002688/BBM dated 25th October 2018).

University Grants Commission, New Delhi for financial support under the UGC-SAP-DRS Phase-II scheme sanctioned to Department of Biochemistry, Shivaji University, Kolhapur.

Department of Science and Technology, Government of India, New Delhi for financial support through DST-PURSE-Phase II (Ref no. SR/PURSE-PHASE-II/24(C) dated 8/3/2018].

Structural Bioinformatics unit, Department of Biochemistry, Shivaji University, Kolhapur and Department of Microbiology, Shivaji University, Kolhapur and for extending the laboratory facilities

SSB is thankful to SARTHI for providing fellowship

All authors are thankful to Computer centre, Shivaji University, Kolhapur for providing necessary computational facilities.

History

Email Address of Submitting Author

kds_biochem@unishivaji.ac.in

Institution

Department of Biochemistry, Shivaji University, Kolhapur, Maharashtra, India

Country

India

ORCID For Submitting Author

0000-0003-0156-7466

Declaration of Conflict of Interest

No conflict of interest

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