8Z46
SARS-CoV-2 3CL protease (3CL pro) in complex with a novel inhibitor
This is a non-PDB format compatible entry.
Summary for 8Z46
| Entry DOI | 10.2210/pdb8z46/pdb |
| Descriptor | 3C-like proteinase nsp5, (2~{S})-~{N}-(3-azanyl-3-oxidanylidene-propyl)-4-[4-[[(1~{S})-1-(2-chlorophenyl)-3-oxidanyl-propyl]amino]-6-(methylamino)-1,3,5-triazin-2-yl]-1-ethanoyl-piperazine-2-carboxamide (3 entities in total) |
| Functional Keywords | sars-cov-2 3cl protease, inhibitor, complex, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 34359.56 |
| 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 (1.57 Å) |
Structure validation
Download full validation report
