5SOL

PanDDA analysis group deposition -- Crystal structure of SARS-CoV-2 NSP3 macrodomain in complex with ZINC000910475722 - (S,R) isomer

Summary for 5SOL

• Entry DOI: 10.2210/pdb5sol/pdb
• Group deposition: PanDDA analysis group deposition of SARS-CoV-2 NSP3 macrodomain ligand screen (G_1002236)
• Descriptor: Non-structural protein 3, (8S)-8-fluoro-6-(6-{[(2R)-2-hydroxypropyl]amino}pyrimidin-4-yl)-6-azaspiro[3.4]octane-8-carboxylic acid (3 entities in total)
• Functional Keywords: macrodomain, adp-ribose, sars-cov-2, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 2
• Total formula weight: 36681.88

Authors

Correy, G.J.,Fraser, J.S. (deposition date: 2022-06-09, release date: 2022-07-13, Last modification date: 2023-09-20)

Primary citation

Gahbauer, S.,Correy, G.J.,Schuller, M.,Ferla, M.P.,Doruk, Y.U.,Rachman, M.,Wu, T.,Diolaiti, M.,Wang, S.,Neitz, R.J.,Fearon, D.,Radchenko, D.S.,Moroz, Y.S.,Irwin, J.J.,Renslo, A.R.,Taylor, J.C.,Gestwicki, J.E.,von Delft, F.,Ashworth, A.,Ahel, I.,Shoichet, B.K.,Fraser, J.S.
Iterative computational design and crystallographic screening identifies potent inhibitors targeting the Nsp3 macrodomain of SARS-CoV-2.
Proc.Natl.Acad.Sci.USA, 120:e2212931120-e2212931120, 2023

PubMed Abstract: The nonstructural protein 3 (NSP3) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) contains a conserved macrodomain enzyme (Mac1) that is critical for pathogenesis and lethality. While small-molecule inhibitors of Mac1 have great therapeutic potential, at the outset of the COVID-19 pandemic, there were no well-validated inhibitors for this protein nor, indeed, the macrodomain enzyme family, making this target a pharmacological orphan. Here, we report the structure-based discovery and development of several different chemical scaffolds exhibiting low- to sub-micromolar affinity for Mac1 through iterations of computer-aided design, structural characterization by ultra-high-resolution protein crystallography, and binding evaluation. Potent scaffolds were designed with in silico fragment linkage and by ultra-large library docking of over 450 million molecules. Both techniques leverage the computational exploration of tangible chemical space and are applicable to other pharmacological orphans. Overall, 160 ligands in 119 different scaffolds were discovered, and 153 Mac1-ligand complex crystal structures were determined, typically to 1 Å resolution or better. Our analyses discovered selective and cell-permeable molecules, unexpected ligand-mediated conformational changes within the active site, and key inhibitor motifs that will template future drug development against Mac1.

PubMed: 36598939
DOI: 10.1073/pnas.2212931120

Experimental method

X-RAY DIFFRACTION (1.05 Å)