7N44
Crystal structure of the SARS-CoV-2 (2019-NCoV) main protease in complex with 5-(3-{3-chloro-5-[(5-methyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-oxo-2H-[1,3'-bipyridin]-5-yl)pyrimidine-2,4(1H,3H)-dione (compound 13)
Summary for 7N44
| Entry DOI | 10.2210/pdb7n44/pdb |
| Descriptor | 3C-like proteinase, 5-(3-{3-chloro-5-[(5-methyl-1,3-thiazol-4-yl)methoxy]phenyl}-2-oxo-2H-[1,3'-bipyridin]-5-yl)pyrimidine-2,4(1H,3H)-dione (3 entities in total) |
| Functional Keywords | novel coronavirus, antiviral, drug design, viral protein, hydrolase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2) |
| Total number of polymer chains | 1 |
| Total formula weight | 34345.51 |
| Authors | Reilly, R.A.,Zhang, C.H.,Deshmukh, M.G.,Ippolito, J.A.,Hollander, K.,Jorgensen, W.L.,Anderson, K.S. (deposition date: 2021-06-03, release date: 2021-07-21, Last modification date: 2023-10-18) |
| Primary citation | Zhang, C.H.,Spasov, K.A.,Reilly, R.A.,Hollander, K.,Stone, E.A.,Ippolito, J.A.,Liosi, M.E.,Deshmukh, M.G.,Tirado-Rives, J.,Zhang, S.,Liang, Z.,Miller, S.J.,Isaacs, F.,Lindenbach, B.D.,Anderson, K.S.,Jorgensen, W.L. Optimization of Triarylpyridinone Inhibitors of the Main Protease of SARS-CoV-2 to Low-Nanomolar Antiviral Potency. Acs Med.Chem.Lett., 12:1325-1332, 2021 Cited by PubMed Abstract: Non-covalent inhibitors of the main protease (M) of SARS-CoV-2 having a pyridinone core were previously reported with IC values as low as 0.018 μM for inhibition of enzymatic activity and EC values as low as 0.8 μM for inhibition of viral replication in Vero E6 cells. The series has now been further advanced by consideration of placement of substituted five-membered-ring heterocycles in the S4 pocket of M and N-methylation of a uracil ring. Free energy perturbation calculations provided guidance on the choice of the heterocycles, and protein crystallography confirmed the desired S4 placement. Here we report inhibitors with EC values as low as 0.080 μM, while remdesivir yields values of 0.5-2 μM in side-by-side testing with infectious SARS-CoV-2. A key factor in the improvement is enhanced cell permeability, as reflected in PAMPA measurements. Compounds and are particularly promising as potential therapies for COVID-19, featuring IC values of 0.044-0.061 μM, EC values of ca. 0.1 μM, good aqueous solubility, and no cytotoxicity. PubMed: 34408808DOI: 10.1021/acsmedchemlett.1c00326 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.94 Å) |
Structure validation
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