Journal Article

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

Gerstberger, Thomas, Schmalhorst, Philipp S., Magarkar, Aniket, Jandova, Zuzana, Kousek, Roland, Böttcher, Jark, Greb, Peter, Mayer, Moriz, Combs, Steven A., Westermaier, Yvonne, Hoenke, Christoph, Kothiwale, Sandeepkumar, Pape, Richard, Smethurst, Christian Alan Paul, Weinstabl, Harald, McConnell, Darryl B., Waterson, Alex G., Meiler, Jens, Bader, Gerd, Moretti, Rocco, Bergner, Andreas, Biberger, Tobias, Scott, Thomas, Phul, Saksham, Fuchs, Julian E.

2025

Overview

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. Citizen science taps the efforts of non-experts. Here, authors describe Drugit, an extension of the crowdsourcing game Foldit, and its use in designing a non-peptide binder of Von Hippel Lindau E3 ligase for use with proteolysis targeting chimeras.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/114/2248 / 631/45/468 / 631/535/1267 / 639/638/309/2420 / Binders / Chimeras / Crowdsourcing / Crowdsourcing - methods / Crystal structure / Crystallography, X-Ray / Design / Drug Design / Drug development / Drug Discovery - methods / Humanities and Social Sciences / Humans / Models, Molecular / multidisciplinary / NMR / Nuclear magnetic resonance / Protein Binding / Proteolysis / Science / Science (multidisciplinary) / Scientists / Small Molecule Libraries - chemistry / Small Molecule Libraries - pharmacology / Ubiquitin-protein ligase / Von Hippel-Lindau Tumor Suppressor Protein - chemistry / Von Hippel-Lindau Tumor Suppressor Protein - metabolism