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; Aleshin Dmitry Alekseevich; Walter Barmettler; Krzysztof Bogusz; Alexander Boykov; Andrew Cai; Jeffrey Michael Canfield; Andy M. Chen; Keith Clayton; Alan Roger Coral; Martin Dickel; Harald Feldmann; Lezhe Gao; Thomas J. George; Kevin M. Gildea; Gregory T. Hansen; Alyssa Joy Higgins; Renton Braden Mathew Innes; Bruno Kestemont; Allen Lubow; George Victor McIlvaine; Ian James McNaughton; Cédric Partinico; Vincent Pit; Alexa Sen; Michael Simon; Vera Simon; Robert Spearing; Bora Tastan; Stephen Vincent; Linda Wei; Jonathan Weinberg; Kevin D. Wells; Douglas Craig Wheeler; Ulas Yeginer; Scott J. Zaccanelli; Carlos Zambrano-Bukonja; Alex G. Waterson; Harald Weinstabl; Darryl B. McConnell; Jens Meiler; Jark Böttcher; Rocco Moretti

doi:10.1038/s41467-025-58406-0

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

T Thomas Scott C Christian Alan Paul Smethurst Y Yvonne Westermaier M Moriz Mayer P Peter Greb R Roland Kousek T Tobias Biberger G Gerd Bader Z Zuzana Jandova P Philipp S. Schmalhorst J Julian E. Fuchs A Aniket Magarkar C Christoph Hoenke T Thomas Gerstberger S Steven A. Combs R Richard Pape S Saksham Phul S Sandeepkumar Kothiwale A Andreas Bergner A Aleshin Dmitry Alekseevich W Walter Barmettler K Krzysztof Bogusz A Alexander Boykov A Andrew Cai J Jeffrey Michael Canfield A Andy M. Chen K Keith Clayton A Alan Roger Coral M Martin Dickel H Harald Feldmann L Lezhe Gao T Thomas J. George K Kevin M. Gildea G Gregory T. Hansen A Alyssa Joy Higgins R Renton Braden Mathew Innes B Bruno Kestemont A Allen Lubow G George Victor McIlvaine I Ian James McNaughton C Cédric Partinico V Vincent Pit A Alexa Sen M Michael Simon V Vera Simon R Robert Spearing B Bora Tastan S Stephen Vincent L Linda Wei J Jonathan Weinberg K Kevin D. Wells D Douglas Craig Wheeler U Ulas Yeginer S Scott J. Zaccanelli C Carlos Zambrano-Bukonja A Alex G. Waterson H Harald Weinstabl D Darryl B. McConnell J Jens Meiler J Jark Böttcher R Rocco Moretti

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.

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Article Details

Journal Nature Communications

Volume / Issue Vol. 16, Issue 1

Published April 14, 2025

DOI 10.1038/s41467-025-58406-0

ISSN 2041-1723

Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio

ISSN: 2041-1723 Open Access Life Sciences

Authors (61)

T

Thomas Scott

C

Christian Alan Paul Smethurst

Y

Yvonne Westermaier

M

Moriz Mayer

P

Peter Greb

R

Roland Kousek

T

Tobias Biberger

G

Gerd Bader

Z

Zuzana Jandova

P

Philipp S. Schmalhorst

J

Julian E. Fuchs

A

Aniket Magarkar

C

Christoph Hoenke

T

Thomas Gerstberger

S

Steven A. Combs

R

Richard Pape

S

Saksham Phul

S

Sandeepkumar Kothiwale

A

Andreas Bergner

A

Aleshin Dmitry Alekseevich

W

Walter Barmettler

K

Krzysztof Bogusz

A

Alexander Boykov

A

Andrew Cai

J

Jeffrey Michael Canfield

A

Andy M. Chen

K

Keith Clayton

A

Alan Roger Coral

M

Martin Dickel

H

Harald Feldmann

L

Lezhe Gao

T

Thomas J. George

K

Kevin M. Gildea

G

Gregory T. Hansen

A

Alyssa Joy Higgins

R

Renton Braden Mathew Innes

B

Bruno Kestemont

A

Allen Lubow

G

George Victor McIlvaine

I

Ian James McNaughton

C

Cédric Partinico

V

Vincent Pit

A

Alexa Sen

M

Michael Simon

V

Vera Simon

R

Robert Spearing

B

Bora Tastan

S

Stephen Vincent

L

Linda Wei

J

Jonathan Weinberg

K

Kevin D. Wells

D

Douglas Craig Wheeler

U

Ulas Yeginer

S

Scott J. Zaccanelli

C

Carlos Zambrano-Bukonja

A

Alex G. Waterson

H

Harald Weinstabl

D

Darryl B. McConnell

J

Jens Meiler

J

Jark Böttcher

R

Rocco Moretti

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

Abstract

Article Details

Journal Info

Authors (61)

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