9C8Q
Co-structure of Main Protease of SARS-CoV-2 (COVID-19) with covalent inhibitor
This is a non-PDB format compatible entry.
Summary for 9C8Q
| Entry DOI | 10.2210/pdb9c8q/pdb |
| Descriptor | 3C-like proteinase nsp5, (7P,8S)-3-cyclohexyl-7-(3-methylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine (3 entities in total) |
| Functional Keywords | hydrolase, main protease, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 34117.92 |
| Authors | Knapp, M.S.,Ornelas, E. (deposition date: 2024-06-12, release date: 2024-10-16, Last modification date: 2024-10-23) |
| Primary citation | Barkan, D.T.,Garland, K.,Zhang, L.,Eastman, R.T.,Hesse, M.,Knapp, M.,Ornelas, E.,Tang, J.,Cortopassi, W.A.,Wang, Y.,King, F.,Jia, W.,Nguyen, Z.,Frank, A.O.,Chan, R.,Fang, E.,Fuller, D.,Busby, S.,Carias, H.,Donahue, K.,Tandeske, L.,Diagana, T.T.,Jarrousse, N.,Moser, H.,Sarko, C.,Dovala, D.,Moquin, S.,Marx, V.M. Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness. J.Med.Chem., 67:17454-17471, 2024 Cited by PubMed Abstract: The COVID-19 pandemic highlights the ongoing risk of zoonotic transmission of coronaviruses to global health. To prepare for future pandemics, it is essential to develop effective antivirals targeting a broad range of coronaviruses. Targeting the essential and clinically validated coronavirus main protease (M), we constructed a structurally diverse M panel by clustering all known coronavirus sequences by M active site sequence similarity. Through screening, we identified a potent covalent inhibitor that engaged the catalytic cysteine of SARS-CoV-2 Mpro and used structure-based medicinal chemistry to develop compounds in the pyrazolopyrimidine sulfone series that exhibit submicromolar activity against multiple M homologues. Additionally, we solved the first X-ray cocrystal structure of M from the human-infecting OC43 coronavirus, providing insights into potency differences among compound-target pairs. Overall, the chemical compounds described in this study serve as starting points for the development of antivirals with broad-spectrum activity, enhancing our preparedness for emerging human-infecting coronaviruses. PubMed: 39332817DOI: 10.1021/acs.jmedchem.4c01404 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.692 Å) |
Structure validation
Download full validation report
