Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking
The papain-like protease (PLpro) found in coronaviruses that can be transmitted from animals to humans is a critical target in respiratory diseases linked to Severe Acute Respiratory Syndrome (SARS-CoV). Researchers have proposed designing PLpro inhibitors. In this study, a set of 89 compounds, incl...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-03-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2024.1374364/full |
| _version_ | 1797243089648091136 |
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| author | Jorge Luis Valdés-Albuernes Erbio Díaz-Pico Sergio Alfaro Julio Caballero |
| author_facet | Jorge Luis Valdés-Albuernes Erbio Díaz-Pico Sergio Alfaro Julio Caballero |
| author_sort | Jorge Luis Valdés-Albuernes |
| collection | DOAJ |
| description | The papain-like protease (PLpro) found in coronaviruses that can be transmitted from animals to humans is a critical target in respiratory diseases linked to Severe Acute Respiratory Syndrome (SARS-CoV). Researchers have proposed designing PLpro inhibitors. In this study, a set of 89 compounds, including recently reported 2-phenylthiophenes with nanomolar inhibitory potency, were investigated as PLpro noncovalent inhibitors using advanced molecular modeling techniques. To develop the work with these inhibitors, multiple structures of the SARS-CoV-2 PLpro binding site were generated using a molecular sampling method. These structures were then clustered to select a group that represents the flexibility of the site. Subsequently, models of the protein-ligand complexes were created for the set of inhibitors within the chosen conformations. The quality of the complex models was assessed using LigRMSD software to verify similarities in the orientations of the congeneric series and interaction fingerprints to determine the recurrence of chemical interactions. With the multiple models constructed, a protocol was established to choose one per ligand, optimizing the correlation between the calculated docking energy values and the biological activities while incorporating the effect of the binding site’s flexibility. A strong correlation (R2 = 0.922) was found when employing this flexible docking protocol. |
| first_indexed | 2024-04-24T18:49:34Z |
| format | Article |
| id | doaj.art-6be677a0d8cf498ab285388331a494e6 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-04-24T18:49:34Z |
| publishDate | 2024-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-6be677a0d8cf498ab285388331a494e62024-03-27T04:25:37ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2024-03-011110.3389/fmolb.2024.13743641374364Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-dockingJorge Luis Valdés-AlbuernesErbio Díaz-PicoSergio AlfaroJulio CaballeroThe papain-like protease (PLpro) found in coronaviruses that can be transmitted from animals to humans is a critical target in respiratory diseases linked to Severe Acute Respiratory Syndrome (SARS-CoV). Researchers have proposed designing PLpro inhibitors. In this study, a set of 89 compounds, including recently reported 2-phenylthiophenes with nanomolar inhibitory potency, were investigated as PLpro noncovalent inhibitors using advanced molecular modeling techniques. To develop the work with these inhibitors, multiple structures of the SARS-CoV-2 PLpro binding site were generated using a molecular sampling method. These structures were then clustered to select a group that represents the flexibility of the site. Subsequently, models of the protein-ligand complexes were created for the set of inhibitors within the chosen conformations. The quality of the complex models was assessed using LigRMSD software to verify similarities in the orientations of the congeneric series and interaction fingerprints to determine the recurrence of chemical interactions. With the multiple models constructed, a protocol was established to choose one per ligand, optimizing the correlation between the calculated docking energy values and the biological activities while incorporating the effect of the binding site’s flexibility. A strong correlation (R2 = 0.922) was found when employing this flexible docking protocol.https://www.frontiersin.org/articles/10.3389/fmolb.2024.1374364/fullpapain-like proteasePLpro inhibitorsSARS-CoV-2docking energy-activity correlationflexible molecular dockingmolecular dynamics |
| spellingShingle | Jorge Luis Valdés-Albuernes Erbio Díaz-Pico Sergio Alfaro Julio Caballero Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking Frontiers in Molecular Biosciences papain-like protease PLpro inhibitors SARS-CoV-2 docking energy-activity correlation flexible molecular docking molecular dynamics |
| title | Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking |
| title_full | Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking |
| title_fullStr | Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking |
| title_full_unstemmed | Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking |
| title_short | Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking |
| title_sort | modeling of noncovalent inhibitors of the papain like protease plpro from sars cov 2 considering the protein flexibility by using molecular dynamics and cross docking |
| topic | papain-like protease PLpro inhibitors SARS-CoV-2 docking energy-activity correlation flexible molecular docking molecular dynamics |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2024.1374364/full |
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