Coronavirus Inhibitors Targeting nsp16
During the past three decades, humans have been confronted with different new coronavirus outbreaks. Since the end of the year 2019, COVID-19 threatens the world as a rapidly spreading infectious disease. For this work, we targeted the non-structural protein 16 (nsp16) as a key protein of SARS-CoV-2...
| Main Authors: | , , , , , |
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/3/988 |
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| author | Ejlal A. Omer Sara Abdelfatah Max Riedl Christian Meesters Andreas Hildebrandt Thomas Efferth |
| author_facet | Ejlal A. Omer Sara Abdelfatah Max Riedl Christian Meesters Andreas Hildebrandt Thomas Efferth |
| author_sort | Ejlal A. Omer |
| collection | DOAJ |
| description | During the past three decades, humans have been confronted with different new coronavirus outbreaks. Since the end of the year 2019, COVID-19 threatens the world as a rapidly spreading infectious disease. For this work, we targeted the non-structural protein 16 (nsp16) as a key protein of SARS-CoV-2, SARS-CoV-1 and MERS-CoV to develop broad-spectrum inhibitors of nsp16. Computational methods were used to filter candidates from a natural product-based library of 224,205 compounds obtained from the ZINC database. The binding of the candidates to nsp16 was assessed using virtual screening with VINA LC, and molecular docking with AutoDock 4.2.6. The top 9 compounds were bound to the nsp16 protein of SARS-CoV-2, SARS-CoV-1, and MERS-CoV with the lowest binding energies (LBEs) in the range of −9.0 to −13.0 kcal with VINA LC. The AutoDock-based LBEs for nsp16 of SARS-CoV-2 ranged from −11.42 to −16.11 kcal/mol with predicted inhibition constants (pKi) from 0.002 to 4.51 nM, the natural substrate S-adenosyl methionine (SAM) was used as control. In silico results were verified by microscale thermophoresis as in vitro assay. The candidates were investigated further for their cytotoxicity in normal MRC-5 lung fibroblasts to determine their therapeutic indices. Here, the IC<sub>50</sub> values of all three compounds were >10 µM. In summary, we identified three novel SARS-CoV-2 inhibitors, two of which showed broad-spectrum activity to nsp16 in SARS-CoV-2, SARS-CoV-1, and MERS-CoV. All three compounds are coumarin derivatives that contain chromen-2-one in their scaffolds. |
| first_indexed | 2024-03-11T09:34:49Z |
| format | Article |
| id | doaj.art-e1e457a67b0f4cd8981dd62f217541d6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T09:34:49Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-e1e457a67b0f4cd8981dd62f217541d62023-11-16T17:26:03ZengMDPI AGMolecules1420-30492023-01-0128398810.3390/molecules28030988Coronavirus Inhibitors Targeting nsp16Ejlal A. Omer0Sara Abdelfatah1Max Riedl2Christian Meesters3Andreas Hildebrandt4Thomas Efferth5Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, GermanyDepartment of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, GermanyInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, 04107 Leipzig, GermanyHigh Performance Computing Group, University of Mainz, 55131 Mainz, GermanyInstitute for Computer Science, University of Mainz, 55131 Mainz, GermanyDepartment of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, GermanyDuring the past three decades, humans have been confronted with different new coronavirus outbreaks. Since the end of the year 2019, COVID-19 threatens the world as a rapidly spreading infectious disease. For this work, we targeted the non-structural protein 16 (nsp16) as a key protein of SARS-CoV-2, SARS-CoV-1 and MERS-CoV to develop broad-spectrum inhibitors of nsp16. Computational methods were used to filter candidates from a natural product-based library of 224,205 compounds obtained from the ZINC database. The binding of the candidates to nsp16 was assessed using virtual screening with VINA LC, and molecular docking with AutoDock 4.2.6. The top 9 compounds were bound to the nsp16 protein of SARS-CoV-2, SARS-CoV-1, and MERS-CoV with the lowest binding energies (LBEs) in the range of −9.0 to −13.0 kcal with VINA LC. The AutoDock-based LBEs for nsp16 of SARS-CoV-2 ranged from −11.42 to −16.11 kcal/mol with predicted inhibition constants (pKi) from 0.002 to 4.51 nM, the natural substrate S-adenosyl methionine (SAM) was used as control. In silico results were verified by microscale thermophoresis as in vitro assay. The candidates were investigated further for their cytotoxicity in normal MRC-5 lung fibroblasts to determine their therapeutic indices. Here, the IC<sub>50</sub> values of all three compounds were >10 µM. In summary, we identified three novel SARS-CoV-2 inhibitors, two of which showed broad-spectrum activity to nsp16 in SARS-CoV-2, SARS-CoV-1, and MERS-CoV. All three compounds are coumarin derivatives that contain chromen-2-one in their scaffolds.https://www.mdpi.com/1420-3049/28/3/988SARS-CoV-2SARS-CoV-1MERS-CoVnsp16natural productspan-inhibitor |
| spellingShingle | Ejlal A. Omer Sara Abdelfatah Max Riedl Christian Meesters Andreas Hildebrandt Thomas Efferth Coronavirus Inhibitors Targeting nsp16 Molecules SARS-CoV-2 SARS-CoV-1 MERS-CoV nsp16 natural products pan-inhibitor |
| title | Coronavirus Inhibitors Targeting nsp16 |
| title_full | Coronavirus Inhibitors Targeting nsp16 |
| title_fullStr | Coronavirus Inhibitors Targeting nsp16 |
| title_full_unstemmed | Coronavirus Inhibitors Targeting nsp16 |
| title_short | Coronavirus Inhibitors Targeting nsp16 |
| title_sort | coronavirus inhibitors targeting nsp16 |
| topic | SARS-CoV-2 SARS-CoV-1 MERS-CoV nsp16 natural products pan-inhibitor |
| url | https://www.mdpi.com/1420-3049/28/3/988 |
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