Figure 1. Crowdsourcing rapidly identified novel chemotype scaffolds by merging fragment hits.

A: A Diamond / XChem fragment screen that initiated this SARS-CoV-2 Mpro inhibitor discovery campaign generated 58 hits that completely cover the Mpro active site, with a variety of chemotypes engaging each pocket; 1495 x-ray datasets were collected and 78 solved structures for hits were publicly posted(20).

The peptidomimetic N3 ligand is shown at left for comparison to indicate natural substrate engagement in the binding site, defining the peptide sidechain numbering scheme used throughout this work. The nucleophilic Cys145 reacts with the scissile peptide bond between P1 and P1’; His41-Cys145 form a catalytic dyad whose coupled charge states shuttle between zwitterionic and neutral states (92).

B: On March 18th 2020, the COVID Moonshot set up a crowdsourcing website to empower scientists across the globe to contribute molecule designs. The number of designs actioned for synthesis each quarter (except for the 2020Q2 which is shown per-month in brackets) is shown, subdivided by the region of the submitter of the design idea. The total number of unique submitters that contributed actioned designs for that quarter is shown on top of the bars.

C: Many submissions, such as TRY-UNI-714a760b-6, exploited spatially overlapping fragment hits to design potent leads that are synthetically facile.

D: Experimental biochemical potency of designs broken down by submission group. Multiple submissions in 2020 from the community were more potent than the best designs from the core team as seen for the top three chloroacetamide structures (left) and non-covalent structures (right).

E: Distribution of synthetic accessibility scores for designs contributed by the core team and the community. The concern that community submissions may be of poor quality is not supported by the fact that these were as synthetic accessible as those designed by the core team (median: community 0.17 core 0.13,). Half of the outliers (SAScore = 1) were primarily natural products, which are hard to achieve via organic chemistry.