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

11 May 2023, Version 1

Abstract

Given the role of human intuition in current drug design efforts, crowd-sourced 'citizen scientist' games have the potential to greatly expand the pool of potential drug designers. Here, we introduce ‘Drugit', the small molecule design mode of the online ‘citizen science’ game Foldit. We demonstrate its utility for design with a use case to identify novel binders to the von Hippel Lindau E3 ligase. Several thousand molecule suggestions were obtained from players in a series of 10 puzzle rounds. The proposed molecules were then evaluated by in silico methods and by an expert panel and selected candidates were synthesized and tested. One of these molecules, designed by a player, showed dose-dependent shift perturbations in protein-observed NMR experiments. The co-crystal structure in complex with the E3 ligase revealed that the observed binding mode matched in major parts 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.

Keywords

citizen science
PROTAC

Supplementary materials

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Supplemental Information
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Supplemental figures, supplemental methods, synthesis details, and compound listing.
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All Player Designed Compounds
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All compounds designed by Foldit players, prior to filtering.
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Compounds passing preliminary filtering
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Compounds passing the preliminary filtering.
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Comment number 1, Lezhe Gao: Dec 08, 2023, 08:46

Being as a part of the Foldit Players, I had add this paper to my orcid account