Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike protein
The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for viral infection. The interaction of its receptor-binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2) protein is required for the virus to enter the host cell. We identified RBD bin...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037023001290 |
| _version_ | 1797384123049836544 |
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| author | M. Ghoula S. Naceri S. Sitruk D. Flatters G. Moroy A.C. Camproux |
| author_facet | M. Ghoula S. Naceri S. Sitruk D. Flatters G. Moroy A.C. Camproux |
| author_sort | M. Ghoula |
| collection | DOAJ |
| description | The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for viral infection. The interaction of its receptor-binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2) protein is required for the virus to enter the host cell. We identified RBD binding sites to block its function with inhibitors by combining the protein structural flexibility with machine learning analysis. Molecular dynamics simulations were performed on unbound or ACE2-bound RBD conformations. Pockets estimation, tracking and druggability prediction were performed on a large sample of simulated RBD conformations. Recurrent druggable binding sites and their key residues were identified by clustering pockets based on their residue similarity. This protocol successfully identified three druggable sites and their key residues, aiming to target with inhibitors for preventing ACE2 interaction. One site features key residues for direct ACE2 interaction, highlighted using energetic computations, but can be affected by several mutations of the variants of concern. Two highly druggable sites, located between the spike protein monomers interface are promising. One weakly impacted by only one Omicron mutation, could contribute to stabilizing the spike protein in its closed state. The other, currently not affected by mutations, could avoid the activation of the spike protein trimer. |
| first_indexed | 2024-03-08T21:30:56Z |
| format | Article |
| id | doaj.art-375450ddc34746d4a40d40a0fec54687 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-03-08T21:30:56Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-375450ddc34746d4a40d40a0fec546872023-12-21T07:31:17ZengElsevierComputational and Structural Biotechnology Journal2001-03702023-01-012123392351Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike proteinM. Ghoula0S. Naceri1S. Sitruk2D. Flatters3G. Moroy4A.C. Camproux5Université Paris Cité, CNRS, INSERM, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, FranceUniversité Paris Cité, CNRS, INSERM, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, FranceUniversité Paris Cité, CNRS, INSERM, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, FranceUniversité Paris Cité, CNRS, INSERM, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, FranceCorresponding authors.; Université Paris Cité, CNRS, INSERM, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, FranceCorresponding authors.; Université Paris Cité, CNRS, INSERM, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, FranceThe spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for viral infection. The interaction of its receptor-binding domain (RBD) with the human angiotensin-converting enzyme 2 (ACE2) protein is required for the virus to enter the host cell. We identified RBD binding sites to block its function with inhibitors by combining the protein structural flexibility with machine learning analysis. Molecular dynamics simulations were performed on unbound or ACE2-bound RBD conformations. Pockets estimation, tracking and druggability prediction were performed on a large sample of simulated RBD conformations. Recurrent druggable binding sites and their key residues were identified by clustering pockets based on their residue similarity. This protocol successfully identified three druggable sites and their key residues, aiming to target with inhibitors for preventing ACE2 interaction. One site features key residues for direct ACE2 interaction, highlighted using energetic computations, but can be affected by several mutations of the variants of concern. Two highly druggable sites, located between the spike protein monomers interface are promising. One weakly impacted by only one Omicron mutation, could contribute to stabilizing the spike protein in its closed state. The other, currently not affected by mutations, could avoid the activation of the spike protein trimer.http://www.sciencedirect.com/science/article/pii/S2001037023001290SARS-CoV-2Spike proteinStructural flexibilityHot spot residuesPocket trackingBinding site flexibility |
| spellingShingle | M. Ghoula S. Naceri S. Sitruk D. Flatters G. Moroy A.C. Camproux Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike protein Computational and Structural Biotechnology Journal SARS-CoV-2 Spike protein Structural flexibility Hot spot residues Pocket tracking Binding site flexibility |
| title | Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike protein |
| title_full | Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike protein |
| title_fullStr | Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike protein |
| title_full_unstemmed | Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike protein |
| title_short | Identifying promising druggable binding sites and their flexibility to target the receptor-binding domain of SARS-CoV-2 spike protein |
| title_sort | identifying promising druggable binding sites and their flexibility to target the receptor binding domain of sars cov 2 spike protein |
| topic | SARS-CoV-2 Spike protein Structural flexibility Hot spot residues Pocket tracking Binding site flexibility |
| url | http://www.sciencedirect.com/science/article/pii/S2001037023001290 |
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