8TPG
Synthesis, X-Ray Crystallographic and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease
Summary for 8TPG
| Entry DOI | 10.2210/pdb8tpg/pdb |
| Descriptor | Non-structural protein 7, (3R)-N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-3-hydroxybutanamide (3 entities in total) |
| Functional Keywords | non-peptidic inhibitors, inhibitors, sars-cov-2, main protease, mpro, viral protein, viral protein-inhibitor complex, viral protein/inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2) |
| Total number of polymer chains | 1 |
| Total formula weight | 34149.02 |
| Authors | Chua, T.K.,Song, Y. (deposition date: 2023-08-04, release date: 2024-01-24, Last modification date: 2024-02-21) |
| Primary citation | Ashraf-Uz-Zaman, M.,Chua, T.K.,Li, X.,Yao, Y.,Moku, B.K.,Mishra, C.B.,Avadhanula, V.,Piedra, P.A.,Song, Y. Design, Synthesis, X-ray Crystallography, and Biological Activities of Covalent, Non-Peptidic Inhibitors of SARS-CoV-2 Main Protease. Acs Infect Dis., 10:715-731, 2024 Cited by PubMed Abstract: Highly contagious SARS-CoV-2 coronavirus has infected billions of people worldwide with flu-like symptoms since its emergence in 2019. It has caused deaths of several million people. The viral main protease (Mpro) is essential for SARS-CoV-2 replication and therefore a drug target. Several series of covalent inhibitors of Mpro were designed and synthesized. Structure-activity relationship studies show that (1) several chloroacetamide- and epoxide-based compounds targeting Cys145 are potent inhibitors with IC values as low as 0.49 μM and (2) Cys44 of Mpro is not nucleophilic for covalent inhibitor design. High-resolution X-ray studies revealed the protein-inhibitor interactions and mechanisms of inhibition. It is of interest that Cys145 preferably attacks the more hindered C atom of several epoxide inhibitors. Chloroacetamide inhibitor and epoxide inhibitor were found to inhibit cellular SARS-CoV-2 replication with an EC (half-log reduction of virus titer) of 3 and 5 μM. These compounds represent new pharmacological leads for anti-SARS-CoV-2 drug development. PubMed: 38192109DOI: 10.1021/acsinfecdis.3c00565 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.692 Å) |
Structure validation
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