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[Preprint]. 2020 Nov 24:2020.11.24.393405. [Version 1] doi: 10.1101/2020.11.24.393405

Figure 1. Overview of the fragment discovery approach for SARS-CoV-2 Nsp3 Mac1 presented in this study.

Figure 1.

A) Surface representation of Nsp3 Mac1 with ADP-ribose bound (cyan) in a deep and open binding cleft. B) Nsp3 Mac1 possesses ADP-ribosylhydrolase activity which removes ADP-ribosylation modifications attached to host and pathogen targets. ADP-ribose is conjugated through C1 of the distal ribose. C) Summary of the fragment discovery campaign presented in this work. Three fragment libraries were screened by crystallography: two general-purpose (XChem and UCSF), and a third bespoke library of 60 compounds, curated for Mac1 by molecular docking of over 20M fragments. Crystallographic studies identified 214 unique fragments binding to Mac1, while the molecular docking effort yielded in 20 crystallographically confirmed hits. Several crystallographic and docking fragments were validated by ITC, DSF, and an HTRF-based ADPr-peptide displacement assay.