Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site
An important stage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) life cycle is the binding of the spike (S) protein to the angiotensin converting enzyme-2 (ACE2) host cell receptor. Therefore, to explore conserved features in spike protein dynamics and to identify potentially novel...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Journal of Clinical Medicine |
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| Online Access: | https://www.mdpi.com/2077-0383/9/5/1473 |
| _version_ | 1797568016595025920 |
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| author | Umesh Kalathiya Monikaben Padariya Marcos Mayordomo Małgorzata Lisowska Judith Nicholson Ashita Singh Maciej Baginski Robin Fahraeus Neil Carragher Kathryn Ball Juergen Haas Alison Daniels Ted R. Hupp Javier Antonio Alfaro |
| author_facet | Umesh Kalathiya Monikaben Padariya Marcos Mayordomo Małgorzata Lisowska Judith Nicholson Ashita Singh Maciej Baginski Robin Fahraeus Neil Carragher Kathryn Ball Juergen Haas Alison Daniels Ted R. Hupp Javier Antonio Alfaro |
| author_sort | Umesh Kalathiya |
| collection | DOAJ |
| description | An important stage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) life cycle is the binding of the spike (S) protein to the angiotensin converting enzyme-2 (ACE2) host cell receptor. Therefore, to explore conserved features in spike protein dynamics and to identify potentially novel regions for drugging, we measured spike protein variability derived from 791 viral genomes and studied its properties by molecular dynamics (MD) simulation. The findings indicated that S2 subunit (heptad-repeat 1 (HR1), central helix (CH), and connector domain (CD) domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the receptor binding domain (RBD) domain, which is typically targeted in drug discovery programs, exhibits more sequence variability and flexibility. Interpretations from MD simulations suggest that the monomer form of spike protein is in constant motion showing transitions between an “up” and “down” state. In addition, the trimer cavity may function as a “bouncing spring” that may facilitate the homotrimer spike protein interactions with the ACE2 receptor. The feasibility of the trimer cavity as a potential drug target was examined by structure based virtual screening. Several hits were identified that have already been validated or suggested to inhibit the SARS-CoV-2 virus in published cell models. In particular, the data suggest an action mechanism for molecules including Chitosan and macrolides such as the mTOR (mammalian target of Rapamycin) pathway inhibitor Rapamycin. These findings identify a novel small molecule binding-site formed by the spike protein oligomer, that might assist in future drug discovery programs aimed at targeting the coronavirus (CoV) family of viruses. |
| first_indexed | 2024-03-10T19:50:24Z |
| format | Article |
| id | doaj.art-33d6b9c2b6c6490c8c4cac3e07f68487 |
| institution | Directory Open Access Journal |
| issn | 2077-0383 |
| language | English |
| last_indexed | 2024-03-10T19:50:24Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Clinical Medicine |
| spelling | doaj.art-33d6b9c2b6c6490c8c4cac3e07f684872023-11-20T00:26:28ZengMDPI AGJournal of Clinical Medicine2077-03832020-05-0195147310.3390/jcm9051473Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding SiteUmesh Kalathiya0Monikaben Padariya1Marcos Mayordomo2Małgorzata Lisowska3Judith Nicholson4Ashita Singh5Maciej Baginski6Robin Fahraeus7Neil Carragher8Kathryn Ball9Juergen Haas10Alison Daniels11Ted R. Hupp12Javier Antonio Alfaro13International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, PolandInternational Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, PolandInternational Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, PolandInternational Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, PolandSharp Life Science (EU) Limited, Oxford Science Park, Edmund Halley Rd, Oxford OX4 4GB, UKInternational Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, PolandDepartment of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233 Gdansk, PolandInternational Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, PolandInstitute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland EH4 2XR, UKInstitute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland EH4 2XR, UKDepartment of Infectious Disease, Edinburgh, Scotland EH4 2XR, UKDepartment of Infectious Disease, Edinburgh, Scotland EH4 2XR, UKInternational Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, PolandInternational Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, PolandAn important stage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) life cycle is the binding of the spike (S) protein to the angiotensin converting enzyme-2 (ACE2) host cell receptor. Therefore, to explore conserved features in spike protein dynamics and to identify potentially novel regions for drugging, we measured spike protein variability derived from 791 viral genomes and studied its properties by molecular dynamics (MD) simulation. The findings indicated that S2 subunit (heptad-repeat 1 (HR1), central helix (CH), and connector domain (CD) domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the receptor binding domain (RBD) domain, which is typically targeted in drug discovery programs, exhibits more sequence variability and flexibility. Interpretations from MD simulations suggest that the monomer form of spike protein is in constant motion showing transitions between an “up” and “down” state. In addition, the trimer cavity may function as a “bouncing spring” that may facilitate the homotrimer spike protein interactions with the ACE2 receptor. The feasibility of the trimer cavity as a potential drug target was examined by structure based virtual screening. Several hits were identified that have already been validated or suggested to inhibit the SARS-CoV-2 virus in published cell models. In particular, the data suggest an action mechanism for molecules including Chitosan and macrolides such as the mTOR (mammalian target of Rapamycin) pathway inhibitor Rapamycin. These findings identify a novel small molecule binding-site formed by the spike protein oligomer, that might assist in future drug discovery programs aimed at targeting the coronavirus (CoV) family of viruses.https://www.mdpi.com/2077-0383/9/5/1473SARS-CoV-2coronavirus disease 2019 (COVID-19)spike glycoproteinvariabilitymolecular dockingmolecular dynamics |
| spellingShingle | Umesh Kalathiya Monikaben Padariya Marcos Mayordomo Małgorzata Lisowska Judith Nicholson Ashita Singh Maciej Baginski Robin Fahraeus Neil Carragher Kathryn Ball Juergen Haas Alison Daniels Ted R. Hupp Javier Antonio Alfaro Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site Journal of Clinical Medicine SARS-CoV-2 coronavirus disease 2019 (COVID-19) spike glycoprotein variability molecular docking molecular dynamics |
| title | Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site |
| title_full | Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site |
| title_fullStr | Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site |
| title_full_unstemmed | Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site |
| title_short | Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site |
| title_sort | highly conserved homotrimer cavity formed by the sars cov 2 spike glycoprotein a novel binding site |
| topic | SARS-CoV-2 coronavirus disease 2019 (COVID-19) spike glycoprotein variability molecular docking molecular dynamics |
| url | https://www.mdpi.com/2077-0383/9/5/1473 |
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