Summary for 9DDF
| Entry DOI | 10.2210/pdb9ddf/pdb |
| Descriptor | 3C-like proteinase nsp5, N-{(3S,4S)-1-[(4S)-imidazo[1,5-a]pyridine-8-carbonyl]-4-phenylpiperidin-3-yl}-1H-pyrrole-2-carboxamide (3 entities in total) |
| Functional Keywords | covalent inhibitor, protease, coronavirus, antiviral, viral protein |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 1 |
| Total formula weight | 34239.02 |
| Authors | Bell, J.A. (deposition date: 2024-08-28, release date: 2025-09-10, Last modification date: 2025-11-05) |
| Primary citation | Okabe, A.,Carney, D.W.,Tawada, M.,Akther, T.,Aida, J.,Takagi, T.,Dougan, D.R.,Leffler, A.E.,Bell, J.A.,Frye, L.,Hickey, E.R.,Komandla, M.,Tao, W.,Selimkhanov, J.,Yonemori, K.,Chang, E.,Saikatendu, K.,Ochida, A. Discovery of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 Main Protease through Computer-Aided Drug Design. J.Med.Chem., 68:21330-21345, 2025 Cited by PubMed Abstract: The COVID-19 pandemic has highlighted a clear need to ensure rapid and equitable global access to health interventions in preparation for future coronavirus-driven pandemics. Here, we report the discovery of highly potent noncovalent inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) with pan-coronavirus (pan-CoV) Mpro inhibition through computer-aided drug design. Virtual screening led to the identification of a noncovalent hit compound with a piperazine core. Structure-guided scaffold morphing provided a novel trisubstituted piperidine core. Free energy perturbation (FEP)-guided designs, with induced-fit of Met49/Met165 and Gln189, resulted in the identification of highly potent compound , which exhibits pan-CoV Mpro inhibition and cellular antiviral efficacy against the SARS-CoV-2 omicron variant. The optimized lead compound was characterized by in vitro ADME/Tox assays and in vivo mouse pharmacokinetics. These findings suggest that compound could be an addition to the repertoire of tools used to support future pandemic preparedness. PubMed: 41076627DOI: 10.1021/acs.jmedchem.5c01199 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.549 Å) |
Structure validation
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