Drugit: crowd-sourcing molecular design of non-peptidic VHL binders

Thomas Scott, Christian Alan Paul Smethurst, Yvonne Westermaier, Moriz Mayer, Peter Greb, Roland Kousek, Tobias Biberger, Gerd Bader, Zuzana Jandova, Philipp S. Schmalhorst, Julian E. Fuchs, Aniket Magarkar, Christoph Hoenke, Thomas Gerstberger, Steven A. Combs, Richard Pape, Saksham Phul, Sandeepkumar Kothiwale, Andreas Bergner, Alex G. Waterson, Harald Weinstabl, Darryl B. McConnell, Jens Meiler (), Jark Böttcher () and Rocco Moretti ()
Additional contact information
Thomas Scott: Vanderbilt University
Christian Alan Paul Smethurst: Boehringer Ingelheim RCV
Yvonne Westermaier: Boehringer Ingelheim RCV
Moriz Mayer: Boehringer Ingelheim RCV
Peter Greb: Boehringer Ingelheim RCV
Roland Kousek: Boehringer Ingelheim RCV
Tobias Biberger: Boehringer Ingelheim RCV
Gerd Bader: Boehringer Ingelheim RCV
Zuzana Jandova: Boehringer Ingelheim RCV
Philipp S. Schmalhorst: Boehringer Ingelheim RCV
Julian E. Fuchs: Boehringer Ingelheim RCV
Aniket Magarkar: Boehringer Ingelheim Pharma GmbH & Co. KG
Christoph Hoenke: Boehringer Ingelheim Pharma GmbH & Co. KG
Thomas Gerstberger: Boehringer Ingelheim RCV
Steven A. Combs: Vanderbilt University
Richard Pape: Vanderbilt University
Saksham Phul: Vanderbilt University
Sandeepkumar Kothiwale: Vanderbilt University
Andreas Bergner: Boehringer Ingelheim RCV
Alex G. Waterson: Vanderbilt University
Harald Weinstabl: Boehringer Ingelheim RCV
Darryl B. McConnell: Boehringer Ingelheim RCV
Jens Meiler: Vanderbilt University
Jark Böttcher: Boehringer Ingelheim RCV
Rocco Moretti: Vanderbilt University

Nature Communications, 2025, vol. 16, issue 1, 1-11

Abstract: Abstract Building on the role of human intuition in small molecule drug design, we explored whether crowdsourcing could recruit citizen scientists to this task while in parallel building awareness for this scientific process. Here, we introduce Drugit ( https://drugit.org ), the small molecule design mode of the online citizen science game Foldit. We demonstrate its utility by identifying distinct binders to the von Hippel Lindau E3 ligase. Several thousand molecules were suggested by players in a series of ten puzzle rounds. The proposed molecules were further evaluated in silico and manually by an expert panel. Selected candidates were synthesized and tested. One of these molecules shows dose-dependent shift perturbations in protein-observed NMR experiments. The co-crystal structure in complex with the E3 ligase reveals that the observed binding mode matches the player’s original idea. The completion of one full design cycle is a proof of concept for the Drugit approach and highlights the potential of involving citizen scientists in early drug discovery.

Date: 2025
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DOI: 10.1038/s41467-025-58406-0

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