7HE0
PanDDA analysis group deposition -- Crystal structure of SARS-CoV-2 NSP3 macrodomain in complex with AVI-0003652
This is a non-PDB format compatible entry.
Summary for 7HE0
| Entry DOI | 10.2210/pdb7he0/pdb |
| Group deposition | PanDDA analysis group deposition of SARS-CoV-2 NSP3 macrodomain ligand screen - FrankenROCS hits and analogues of AVI-313 (G_1002304) |
| Descriptor | Non-structural protein 3, trifluoroacetic acid, (R)-phenyl[(2R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-2-yl]methanol, ... (5 entities in total) |
| Functional Keywords | macrodomain, adp-ribose, sars-cov-2, fragment-based drug discovery, viral protein, hydrolase |
| Biological source | Severe acute respiratory syndrome coronavirus 2 |
| Total number of polymer chains | 2 |
| Total formula weight | 36801.36 |
| Authors | |
| Primary citation | Correy, G.J.,Rachman, M.M.,Togo, T.,Gahbauer, S.,Doruk, Y.U.,Stevens, M.G.V.,Jaishankar, P.,Kelley, B.,Goldman, B.,Schmidt, M.,Kramer, T.,Radchenko, D.S.,Moroz, Y.S.,Ashworth, A.,Riley, P.,Shoichet, B.K.,Renslo, A.R.,Walters, W.P.,Fraser, J.S. Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning. Sci Adv, 11:eads7187-eads7187, 2025 Cited by PubMed Abstract: The macrodomain of severe acute respiratory syndrome coronavirus 2 nonstructural protein 3 is required for viral pathogenesis and is an emerging antiviral target. We previously performed an x-ray crystallography-based fragment screen and found submicromolar inhibitors by fragment linking. However, these compounds had poor membrane permeability and liabilities that complicated optimization. Here, we developed a shape-based virtual screening pipeline-FrankenROCS. We screened the Enamine high-throughput collection of 2.1 million compounds, selecting 39 compounds for testing, with the most potent binding with a 130 μM median inhibitory concentration (IC). We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent binding with a 220 μM IC. Further optimization led to analogs with IC values better than 10 μM. This lead series has improved membrane permeability and is poised for optimization. FrankenROCS is a scalable method for fragment linking to exploit synthesis-on-demand libraries. PubMed: 40435250DOI: 10.1126/sciadv.ads7187 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (0.98 Å) |
Structure validation
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