8Z4W
Crystal structures of SARS-CoV-2 papain-like protease in complex with covalent inhibitors
This is a non-PDB format compatible entry.
Summary for 8Z4W
| Entry DOI | 10.2210/pdb8z4w/pdb |
| Descriptor | Non-structural protein 3, 1-[4-[[[4-(isoquinolin-5-ylamino)-6-(methylamino)-1,3,5-triazin-2-yl]amino]methyl]piperidin-1-yl]ethanone, ZINC ION, ... (5 entities in total) |
| Functional Keywords | viral protein-inhibitor complex, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2) |
| Total number of polymer chains | 4 |
| Total formula weight | 145282.54 |
| Authors | |
| Primary citation | Wang, X.,Xiong, L.,Zhu, Y.,Liu, S.,Zhao, W.,Wu, X.,Seydimemet, M.,Li, L.,Ding, P.,Lin, X.,Liu, J.,Wang, X.,Duan, Z.,Lu, W.,Suo, Y.,Cui, M.,Yue, J.,Jin, R.,Zheng, M.,Xu, Y.,Mei, L.,Hu, H.,Lu, X. Covalent DNA-Encoded Library Workflow Drives Discovery of SARS-CoV-2 Nonstructural Protein Inhibitors. J.Am.Chem.Soc., 146:33983-33996, 2024 Cited by PubMed Abstract: The COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple viral proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based covalent inhibitors for the 3-chymotrypsin-like protease (3CL, Nsp5) and the papain-like protease (PL) domains of Nsp3, as well as novel non-nucleoside covalent inhibitors for the nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking and medicinal chemistry led to the development of , a nonpeptide 3CL inhibitor with an IC of 0.34 μM, and , whose crystal structure showed a distinct binding mode within the 3CL active site. The X-ray cocrystal structure of SARS-CoV-2 PL in complex with uncovered a previously unexplored binding site adjacent to the catalytic pocket. Additionally, a non-nucleoside covalent Nsp12 inhibitor achieved a potency of 0.12 μM following comprehensive structure-activity relationship analysis and optimization. Molecular dynamics revealed a potential binding mode. These compounds offer valuable chemical probes for target validation and represent promising candidates for the development of SARS-CoV-2 antiviral therapies. PubMed: 39574309DOI: 10.1021/jacs.4c12992 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.33 Å) |
Structure validation
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