The crystallographic fragment screen against the SARS-CoV-2 Nsp3 macrodomain encompassed multiple fragment libraries: the DSI-poised library, MiniFrags (Astex), FragLites & Peplites (CRUK Newcastle Drug Discovery Unit (Newcastle University)), York3D (University of York), SpotFinder (Hungarian Academy of Sciences) the Edelris Keymical library and the EU OPENSCREEN fragment library.
The screen identified 88 binding events in the four sites of known biological interest (along with the usual artefactual hits that bind to the surface and crystal contacts):
Figure 2. SARS-CoV-2 Nsp3 macrodomain fragment hits. (A) Fragment hits were identified at different sites around the macrodomain crystallographic dimer. Of particular interest are fragments binding to site 1 as being the adenine binding site of the natural ligand ADP-ribose and fragments binding to site 4 as being the substrate binding site which enables macrodomain interactions with ADP-ribosylated host proteins. The macrodomain is shown in surface representation and the fragments as atom-coloured stick model. (B) Overlay of fragments targeting the adenine (right) and substrate (left) binding site of the Nsp3 macrodomain. The natural ligand ADP-ribose in stick/sphere representation was superimposed to the selected structures.
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