Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents
Oxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit of Gram-positive and Gram-negative bacteria. Many crystal structures of the ribosomes with oxazolidinone ligands have been reported in the literature, facilitating structure-based design using m...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/12/3/463 |
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| author | McKenna E. Buckley Audrey R. N. Ndukwe Pramod C. Nair Santu Rana Kathryn E. Fairfull-Smith Neha S. Gandhi |
| author_facet | McKenna E. Buckley Audrey R. N. Ndukwe Pramod C. Nair Santu Rana Kathryn E. Fairfull-Smith Neha S. Gandhi |
| author_sort | McKenna E. Buckley |
| collection | DOAJ |
| description | Oxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit of Gram-positive and Gram-negative bacteria. Many crystal structures of the ribosomes with oxazolidinone ligands have been reported in the literature, facilitating structure-based design using methods such as molecular docking. It would be of great interest to know in advance how well docking methods can reproduce the correct ligand binding modes and rank these correctly. We examined the performance of five molecular docking programs (AutoDock 4, AutoDock Vina, DOCK 6, rDock, and RLDock) for their ability to model ribosomal–ligand interactions with oxazolidinones. Eleven ribosomal crystal structures with oxazolidinones as the ligands were docked. The accuracy was evaluated by calculating the docked complexes’ root-mean-square deviation (RMSD) and the program’s internal scoring function. The rankings for each program based on the median RMSD between the native and predicted were DOCK 6 > AD4 > Vina > RDOCK >> RLDOCK. Results demonstrate that the top-performing program, DOCK 6, could accurately replicate the ligand binding in only four of the eleven ribosomes due to the poor electron density of said ribosomal structures. In this study, we have further benchmarked the performance of the DOCK 6 docking algorithm and scoring in improving virtual screening (VS) enrichment using the dataset of 285 oxazolidinone derivatives against oxazolidinone binding sites in the <i>S. aureus</i> ribosome. However, there was no clear trend between the structure and activity of the oxazolidinones in VS. Overall, the docking performance indicates that the RNA pocket’s high flexibility does not allow for accurate docking prediction, highlighting the need to validate VS. protocols for ligand-RNA before future use. Later, we developed a re-scoring method incorporating absolute docking scores and molecular descriptors, and the results indicate that the descriptors greatly improve the correlation of docking scores and pMIC values. Morgan fingerprint analysis was also used, suggesting that DOCK 6 underpredicted molecules with tail modifications with acetamide, n-methylacetamide, or n-ethylacetamide and over-predicted molecule derivatives with methylamino bits. Alternatively, a ligand-based approach similar to a field template was taken, indicating that each derivative’s tail groups have strong positive and negative electrostatic potential contributing to microbial activity. These results indicate that one should perform VS. campaigns of ribosomal antibiotics with care and that more comprehensive strategies, including molecular dynamics simulations and relative free energy calculations, might be necessary in conjunction with VS. and docking. |
| first_indexed | 2024-03-11T07:01:08Z |
| format | Article |
| id | doaj.art-0a617c4e8114435cb36d70ac9564b85c |
| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-11T07:01:08Z |
| publishDate | 2023-02-01 |
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| series | Antibiotics |
| spelling | doaj.art-0a617c4e8114435cb36d70ac9564b85c2023-11-17T09:13:20ZengMDPI AGAntibiotics2079-63822023-02-0112346310.3390/antibiotics12030463Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial AgentsMcKenna E. Buckley0Audrey R. N. Ndukwe1Pramod C. Nair2Santu Rana3Kathryn E. Fairfull-Smith4Neha S. Gandhi5Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD 4059, AustraliaSchool of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD 4000, AustraliaDiscipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University, Adelaide, SA 5042, AustraliaApplied Artificial Intelligence Institute (A2I2), Deakin University, Geelong, VIC 3220, AustraliaSchool of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD 4000, AustraliaCentre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, QLD 4059, AustraliaOxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit of Gram-positive and Gram-negative bacteria. Many crystal structures of the ribosomes with oxazolidinone ligands have been reported in the literature, facilitating structure-based design using methods such as molecular docking. It would be of great interest to know in advance how well docking methods can reproduce the correct ligand binding modes and rank these correctly. We examined the performance of five molecular docking programs (AutoDock 4, AutoDock Vina, DOCK 6, rDock, and RLDock) for their ability to model ribosomal–ligand interactions with oxazolidinones. Eleven ribosomal crystal structures with oxazolidinones as the ligands were docked. The accuracy was evaluated by calculating the docked complexes’ root-mean-square deviation (RMSD) and the program’s internal scoring function. The rankings for each program based on the median RMSD between the native and predicted were DOCK 6 > AD4 > Vina > RDOCK >> RLDOCK. Results demonstrate that the top-performing program, DOCK 6, could accurately replicate the ligand binding in only four of the eleven ribosomes due to the poor electron density of said ribosomal structures. In this study, we have further benchmarked the performance of the DOCK 6 docking algorithm and scoring in improving virtual screening (VS) enrichment using the dataset of 285 oxazolidinone derivatives against oxazolidinone binding sites in the <i>S. aureus</i> ribosome. However, there was no clear trend between the structure and activity of the oxazolidinones in VS. Overall, the docking performance indicates that the RNA pocket’s high flexibility does not allow for accurate docking prediction, highlighting the need to validate VS. protocols for ligand-RNA before future use. Later, we developed a re-scoring method incorporating absolute docking scores and molecular descriptors, and the results indicate that the descriptors greatly improve the correlation of docking scores and pMIC values. Morgan fingerprint analysis was also used, suggesting that DOCK 6 underpredicted molecules with tail modifications with acetamide, n-methylacetamide, or n-ethylacetamide and over-predicted molecule derivatives with methylamino bits. Alternatively, a ligand-based approach similar to a field template was taken, indicating that each derivative’s tail groups have strong positive and negative electrostatic potential contributing to microbial activity. These results indicate that one should perform VS. campaigns of ribosomal antibiotics with care and that more comprehensive strategies, including molecular dynamics simulations and relative free energy calculations, might be necessary in conjunction with VS. and docking.https://www.mdpi.com/2079-6382/12/3/463molecular dockingoxazolidinonesantibioticsrRNAribosomesre-scoring |
| spellingShingle | McKenna E. Buckley Audrey R. N. Ndukwe Pramod C. Nair Santu Rana Kathryn E. Fairfull-Smith Neha S. Gandhi Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents Antibiotics molecular docking oxazolidinones antibiotics rRNA ribosomes re-scoring |
| title | Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents |
| title_full | Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents |
| title_fullStr | Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents |
| title_full_unstemmed | Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents |
| title_short | Comparative Assessment of Docking Programs for Docking and Virtual Screening of Ribosomal Oxazolidinone Antibacterial Agents |
| title_sort | comparative assessment of docking programs for docking and virtual screening of ribosomal oxazolidinone antibacterial agents |
| topic | molecular docking oxazolidinones antibiotics rRNA ribosomes re-scoring |
| url | https://www.mdpi.com/2079-6382/12/3/463 |
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