8ACD
Crystal structure of SARS-CoV-2 main protease (MPro) in complex with the non-covalent inhibitor GA-17S
Summary for 8ACD
| Entry DOI | 10.2210/pdb8acd/pdb |
| Descriptor | 3C-like proteinase nsp5, (2~{S})-4-[[2,4-bis(oxidanylidene)-1~{H}-pyrimidin-6-yl]carbonyl]-1-(3,4-dichlorophenyl)-~{N}-(thiophen-2-ylmethyl)piperazine-2-carboxamide (3 entities in total) |
| Functional Keywords | sars-cov-2, main protease, non-covalent inhibitor, drug design, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2) |
| Total number of polymer chains | 1 |
| Total formula weight | 34333.92 |
| Authors | Strater, N.,Muller, C.E.,Sylvester, K.,Claff, T.,Weisse, R.H.,Gao, S.,Tollefson, A.E.,Liu, X.,Zhan, P. (deposition date: 2022-07-05, release date: 2022-09-28, Last modification date: 2024-01-31) |
| Primary citation | Gao, S.,Sylvester, K.,Song, L.,Claff, T.,Jing, L.,Woodson, M.,Weisse, R.H.,Cheng, Y.,Schakel, L.,Petry, M.,Gutschow, M.,Schiedel, A.C.,Strater, N.,Kang, D.,Xu, S.,Toth, K.,Tavis, J.,Tollefson, A.E.,Muller, C.E.,Liu, X.,Zhan, P. Discovery and Crystallographic Studies of Trisubstituted Piperazine Derivatives as Non-Covalent SARS-CoV-2 Main Protease Inhibitors with High Target Specificity and Low Toxicity. J.Med.Chem., 65:13343-13364, 2022 Cited by PubMed Abstract: The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to combat the highly infectious variants. The main protease (M) is an promising target for anti-SARS-CoV-2 drug design. Here, we report the discovery of potent non-covalent non-peptide M inhibitors featuring a 1,2,4-trisubstituted piperazine scaffold. We systematically modified the non-covalent hit MCULE-5948770040 by structure-based rational design combined with multi-site binding and privileged structure assembly strategies. The optimized compound inhibits M with high potency (IC = 0.40 μM) and displays excellent antiviral activity (EC = 1.1 μM), being more potent than Remdesivir. Notably, exhibits low cytotoxicity (CC > 100 μM) and excellent target selectivity for SARS-CoV-2 M (IC > 50 μM for cathepsins B, F, K, L, and caspase 3). X-ray co-crystal structures prove that the inhibitors occupy multiple subpockets by critical non-covalent interactions. These studies may provide a basis for developing a more efficient and safer therapy for COVID-19. PubMed: 36107752DOI: 10.1021/acs.jmedchem.2c01146 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.39 Å) |
Structure validation
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