7P2G
Identification of low micromolar SARS-CoV-2 Mpro inhibitors from hits identified by in silico screens
Summary for 7P2G
| Entry DOI | 10.2210/pdb7p2g/pdb |
| Descriptor | 3C-like proteinase, (4~{R})-~{N}-(4-iodophenyl)-2-oxidanylidene-3,4-dihydro-1~{H}-quinoline-4-carboxamide (3 entities in total) |
| Functional Keywords | sars-cov-2, mpro, inhibitor, protease, hydrolase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2) |
| Total number of polymer chains | 1 |
| Total formula weight | 34217.74 |
| Authors | Rempel, S.,Halazonetis, T.D. (deposition date: 2021-07-05, release date: 2022-05-04, Last modification date: 2024-01-31) |
| Primary citation | Rossetti, G.G.,Ossorio, M.A.,Rempel, S.,Kratzel, A.,Dionellis, V.S.,Barriot, S.,Tropia, L.,Gorgulla, C.,Arthanari, H.,Thiel, V.,Mohr, P.,Gamboni, R.,Halazonetis, T.D. Non-covalent SARS-CoV-2 M pro inhibitors developed from in silico screen hits. Sci Rep, 12:2505-2505, 2022 Cited by PubMed Abstract: M, the main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is essential for the viral life cycle. Accordingly, several groups have performed in silico screens to identify M inhibitors that might be used to treat SARS-CoV-2 infections. We selected more than five hundred compounds from the top-ranking hits of two very large in silico screens for on-demand synthesis. We then examined whether these compounds could bind to M and inhibit its protease activity. Two interesting chemotypes were identified, which were further evaluated by characterizing an additional five hundred synthesis on-demand analogues. The compounds of the first chemotype denatured M and were considered not useful for further development. The compounds of the second chemotype bound to and enhanced the melting temperature of M. The most active compound from this chemotype inhibited M in vitro with an IC value of 1 μM and suppressed replication of the SARS-CoV-2 virus in tissue culture cells. Its mode of binding to M was determined by X-ray crystallography, revealing that it is a non-covalent inhibitor. We propose that the inhibitors described here could form the basis for medicinal chemistry efforts that could lead to the development of clinically relevant inhibitors. PubMed: 35169179DOI: 10.1038/s41598-022-06306-4 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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