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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Published by Elsevier Ltd.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152215/ https://www.ncbi.nlm.nih.gov/pubmed/34075338 http://dx.doi.org/10.1016/j.imu.2021.100597 |
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author | Sonawane, Kailas D. Barale, Sagar S. Dhanavade, Maruti J. Waghmare, Shailesh R. Nadaf, Naiem H. Kamble, Subodh A. Mohammed, Ali Abdulmawjood Makandar, Asiya M. Fandilolu, Prayagraj M. Dound, Ambika S. Naik, Nitin M. More, Vikramsinh B. |
author_facet | Sonawane, Kailas D. Barale, Sagar S. Dhanavade, Maruti J. Waghmare, Shailesh R. Nadaf, Naiem H. Kamble, Subodh A. Mohammed, Ali Abdulmawjood Makandar, Asiya M. Fandilolu, Prayagraj M. Dound, Ambika S. Naik, Nitin M. More, Vikramsinh B. |
author_sort | Sonawane, Kailas D. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8152215 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Published by Elsevier Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-81522152021-05-28 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 Sonawane, Kailas D. Barale, Sagar S. Dhanavade, Maruti J. Waghmare, Shailesh R. Nadaf, Naiem H. Kamble, Subodh A. Mohammed, Ali Abdulmawjood Makandar, Asiya M. Fandilolu, Prayagraj M. Dound, Ambika S. Naik, Nitin M. More, Vikramsinh B. Inform Med Unlocked Article 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. Published by Elsevier Ltd. 2021 2021-05-26 /pmc/articles/PMC8152215/ /pubmed/34075338 http://dx.doi.org/10.1016/j.imu.2021.100597 Text en © 2021 Published by Elsevier Ltd. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active. |
spellingShingle | Article Sonawane, Kailas D. Barale, Sagar S. Dhanavade, Maruti J. Waghmare, Shailesh R. Nadaf, Naiem H. Kamble, Subodh A. Mohammed, Ali Abdulmawjood Makandar, Asiya M. Fandilolu, Prayagraj M. Dound, Ambika S. Naik, Nitin M. More, Vikramsinh B. 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152215/ https://www.ncbi.nlm.nih.gov/pubmed/34075338 http://dx.doi.org/10.1016/j.imu.2021.100597 |
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