9GILSummary for 9GIL
| Entry DOI | 10.2210/pdb9gil/pdb |
| Descriptor | 3C-like proteinase nsp5, (7~{R},11~{R},19~{E})-11-[(4-chlorophenyl)methyl]-13-oxa-3,10,23-triazatricyclo[19.3.1.0^{3,7}]pentacosa-1(24),19,21(25),22-tetraene-2,9,12-trione, SULFATE ION, ... (6 entities in total) |
| Functional Keywords | mpro, sars-cov-2, hydrolase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 2 |
| Total formula weight | 69928.19 |
| Authors | Schmitt, A.,Preuss, F.,Prasad, A.,Maskos, K.,Wang, X.,Gotchev, D.,Konz Makino, D.L. (deposition date: 2024-08-19, release date: 2024-11-06, Last modification date: 2024-11-27) |
| Primary citation | Wang, X.,Gotchev, D.,Fan, K.Y.,Vega, M.M.,Mani, N.,McGovern-Gooch, K.,Cuconati, A.,Tercero, B.,Wang, X.,Carpino, P.,Maskos, K.,Centrella, P.A.,Schmitt, A.,Preuss, F.,Prasad, A.,Chen, C.Y.,Clark, M.A.,Guilinger, J.P.,Johnstone, S.,von Konig, K.,Keefe, A.D.,Liu, J.,Turcotte, S.,Zhang, Y.,Konz Makino, D.L.,Lam, A.M.,Cole, A.G.,Sofia, M.J. Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 M pro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants. J.Med.Chem., 67:19623-19667, 2024 Cited by PubMed Abstract: The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M inhibitor was the first such approved therapy. Although M inhibitors of various chemical classes have been reported, they are generally less active against nirmatrelvir-resistant variants and have limited pan-coronavirus potential, presenting a significant human health risk upon future outbreaks. We here present a novel approach and utilized DNA-encoded chemical library screening to identify the noncovalent M inhibitor , which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in lactone with significantly improved antiviral activity. Further optimization led to the potent lactam , which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from other coronaviruses. PubMed: 39453309DOI: 10.1021/acs.jmedchem.4c02009 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.849 Å) |
Structure validation
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