<i>In Silico</i> Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility
The 2019 coronavirus disease (COVID-19) pandemic continues to challenge health care systems worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the cause of global pandemic. Type 2 transmembrane serine protease (TMPRSS2) is important in the cell entry and...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-02-01
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| Series: | Life |
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| Online Access: | https://www.mdpi.com/2075-1729/12/2/231 |
| _version_ | 1827654254175715328 |
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| author | Mohd Zulkifli Salleh Zakuan Zainy Deris |
| author_facet | Mohd Zulkifli Salleh Zakuan Zainy Deris |
| author_sort | Mohd Zulkifli Salleh |
| collection | DOAJ |
| description | The 2019 coronavirus disease (COVID-19) pandemic continues to challenge health care systems worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the cause of global pandemic. Type 2 transmembrane serine protease (TMPRSS2) is important in the cell entry and spread of SARS-CoV-2 and plays a crucial role in the proteolytic cleavage of SARS-CoV-2 spike (S) glycoprotein. Here, using reported structural data, we analyzed the molecular complex of TMPRSS2 and the S glycoprotein and further examined intermolecular interactions of natural TMPRSS2 polymorphic variants. We identified several TMPRSS2 variants that could possibly alter host susceptibility to the SARS-CoV-2 infection. Molecular docking analysis revealed that G462D/G462S variants were predicted to be protective variants, whereas Q438E and S339F variants were predicted to increase susceptibility. In addition, we examined intermolecular interactions between TMPRSS2 and its two potential serine protease inhibitors, camostat mesylate and nafamostat. Further, we investigated the effect of TMPRSS2 variants on these interactions. Our structural analysis revealed that G462D, C297S and S460R variants had possibly altered the interactions with the protease inhibitors. Our results identified important TMPRSS2 variations that could be useful to develop high affinity and personalized drugs for treating COVID-19 patients. |
| first_indexed | 2024-03-09T21:35:46Z |
| format | Article |
| id | doaj.art-dba3f85fd5fc424fbd75554f063e34e6 |
| institution | Directory Open Access Journal |
| issn | 2075-1729 |
| language | English |
| last_indexed | 2024-03-09T21:35:46Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Life |
| spelling | doaj.art-dba3f85fd5fc424fbd75554f063e34e62023-11-23T20:46:08ZengMDPI AGLife2075-17292022-02-0112223110.3390/life12020231<i>In Silico</i> Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 SusceptibilityMohd Zulkifli Salleh0Zakuan Zainy Deris1Department of Medical Microbiology & Parasitology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian 16150, MalaysiaDepartment of Medical Microbiology & Parasitology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian 16150, MalaysiaThe 2019 coronavirus disease (COVID-19) pandemic continues to challenge health care systems worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the cause of global pandemic. Type 2 transmembrane serine protease (TMPRSS2) is important in the cell entry and spread of SARS-CoV-2 and plays a crucial role in the proteolytic cleavage of SARS-CoV-2 spike (S) glycoprotein. Here, using reported structural data, we analyzed the molecular complex of TMPRSS2 and the S glycoprotein and further examined intermolecular interactions of natural TMPRSS2 polymorphic variants. We identified several TMPRSS2 variants that could possibly alter host susceptibility to the SARS-CoV-2 infection. Molecular docking analysis revealed that G462D/G462S variants were predicted to be protective variants, whereas Q438E and S339F variants were predicted to increase susceptibility. In addition, we examined intermolecular interactions between TMPRSS2 and its two potential serine protease inhibitors, camostat mesylate and nafamostat. Further, we investigated the effect of TMPRSS2 variants on these interactions. Our structural analysis revealed that G462D, C297S and S460R variants had possibly altered the interactions with the protease inhibitors. Our results identified important TMPRSS2 variations that could be useful to develop high affinity and personalized drugs for treating COVID-19 patients.https://www.mdpi.com/2075-1729/12/2/231SARS-CoV-2COVID-19TMPRSS2spike proteinpolymorphismssusceptibility |
| spellingShingle | Mohd Zulkifli Salleh Zakuan Zainy Deris <i>In Silico</i> Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility Life SARS-CoV-2 COVID-19 TMPRSS2 spike protein polymorphisms susceptibility |
| title | <i>In Silico</i> Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility |
| title_full | <i>In Silico</i> Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility |
| title_fullStr | <i>In Silico</i> Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility |
| title_full_unstemmed | <i>In Silico</i> Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility |
| title_short | <i>In Silico</i> Molecular Characterization of Human TMPRSS2 Protease Polymorphic Variants and Associated SARS-CoV-2 Susceptibility |
| title_sort | i in silico i molecular characterization of human tmprss2 protease polymorphic variants and associated sars cov 2 susceptibility |
| topic | SARS-CoV-2 COVID-19 TMPRSS2 spike protein polymorphisms susceptibility |
| url | https://www.mdpi.com/2075-1729/12/2/231 |
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