7T44
Structure of SARS-CoV-2 3CL protease in complex with inhibitor 4c
Summary for 7T44
| Entry DOI | 10.2210/pdb7t44/pdb |
| Descriptor | 3C-like proteinase, (1R,2S)-2-[(N-{[(2-azaspiro[3.3]heptan-6-yl)oxy]carbonyl}-L-leucyl)amino]-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, (1S,2S)-1-hydroxy-2-{[N-({[2-(methanesulfonyl)-2-azaspiro[3.3]heptan-6-yl]oxy}carbonyl)-L-leucyl]amino}-3-[(3S)-2-oxopyrrolidin-3-yl]propane-1-sulfonic acid, ... (5 entities in total) |
| Functional Keywords | covid-19, protease, severe acute respiratory syndrome coronavirus 2, sars-cov-2 3cl protease inhhibitors, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 2 |
| Total formula weight | 70606.48 |
| Authors | Liu, L.,Lovell, S.,Battaile, K.P.,Chamandi, S.D.,Kim, Y.,Groutas, W.C.,Chang, K.O. (deposition date: 2021-12-09, release date: 2021-12-22, Last modification date: 2024-10-23) |
| Primary citation | Dampalla, C.S.,Rathnayake, A.D.,Galasiti Kankanamalage, A.C.,Kim, Y.,Perera, K.D.,Nguyen, H.N.,Miller, M.J.,Madden, T.K.,Picard, H.R.,Thurman, H.A.,Kashipathy, M.M.,Liu, L.,Battaile, K.P.,Lovell, S.,Chang, K.O.,Groutas, W.C. Structure-Guided Design of Potent Spirocyclic Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 3C-like Protease. J.Med.Chem., 65:7818-7832, 2022 Cited by PubMed Abstract: The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CL) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CL that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CL and MERS-CoV 3CL that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures. PubMed: 35638577DOI: 10.1021/acs.jmedchem.2c00224 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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