9KR5
Crystal structure of SARS-CoV-2 main protease in complex with compound 3
This is a non-PDB format compatible entry.
Summary for 9KR5
| Entry DOI | 10.2210/pdb9kr5/pdb |
| Descriptor | 3C-like proteinase nsp5, (6~{E})-6-(6-chloranyl-2-methyl-indazol-5-yl)imino-3-[5-[(3~{S})-oxolan-3-yl]oxypyridin-3-yl]-1-[[2,4,5-tris(fluoranyl)phenyl]methyl]-1,3,5-triazinane-2,4-dione (3 entities in total) |
| Functional Keywords | inhibitor, complex, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 33990.99 |
| Authors | |
| Primary citation | Yang, Q.,Huang, X.,Zhang, H.,Sun, J.,Tang, J.,Chen, Z.,Liu, L.,Liu, M.,Sun, Z.,Tang, Z.,Wei, D.,Wang, D.,Wang, Y.,Yan, M.,Zhao, L.,Zhu, A.,Zhong, Y.,Yang, H.,Zhao, Y.,Dai, J.,Shi, Y.,Huang, B.,Zhang, W.,Zhao, J.,Chen, X.,Rao, Z.,Peng, W. Expanding the utilization of binding pockets proves to be effective for noncovalent small molecule inhibitors against SARS-CoV-2 M pro. Eur.J.Med.Chem., 289:117497-117497, 2025 Cited by PubMed Abstract: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and continues to pose serious threats to global public health. The main protease (M) of SARS-CoV-2 is crucial for viral replication and its conservation, making it an attractive drug target. Here, we employed a structure-based drug design strategy to develop and optimize novel inhibitors targeting SARS-CoV-2 M. By fully exploring occupation of the S1, S2, and S3/S4 binding pockets, we identified eight promising inhibitors with half-maximal inhibitory concentration (IC) values below 20 nM. The cocrystal structure of M with compound 10 highlighted the crucial roles of the interactions within the S3/S4 pockets in inhibitor potency enhancement. These findings demonstrated that expanding the utilization of these binding pockets was an effective strategy for developing noncovalent small molecule inhibitors that target SARS-CoV-2 M. Compound 4 demonstrated outstanding in vitro antiviral activity against wild-type SARS-CoV-2 with an EC of 9.4 nM. Moreover, oral treatment with compounds 1 and 9 exhibited excellent antiviral potency and substantially ameliorated virus-induced tissue damage in the lungs of Omicron BA.5-infected K18-human ACE2 (K18-hACE2) transgenic mice, indicating that these novel noncovalent inhibitors could be potential oral agents for the treatment of COVID-19. PubMed: 40090296DOI: 10.1016/j.ejmech.2025.117497 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.92 Å) |
Structure validation
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