Drugit: crowd-sourcing molecular design of non-peptidic VHL binders @NatureComms 1. This paper introduces Drugit, a novel small molecule design interface built into the Foldit citizen science game, enabling non-experts to design protein-targeting molecules using intuitive tools and real-time feedback. 2. Using von Hippel-Lindau (VHL) E3 ligase as a model, players participated in ten weekly puzzle rounds to design non-peptidic VHL binders with improved drug-like properties such as lower polarity and better permeability. 3. Over 6,500 unique compounds were submitted by 160 Foldit players, covering broader chemical space than known VHL ligands. Submissions were filtered and triaged through cheminformatics tools, docking, and expert review. 4. One player-designed compound was synthesized, shown to bind VHL via NMR, and co-crystallized with the protein. The bound structure confirmed key pharmacophores and preserved the intended player-conceived binding mode. 5. Remarkably, the binding compound was designed by a player with no formal medicinal chemistry training, underscoring the potential of gamified citizen science in early drug discovery. 6. The final hit compound features a hydroxy-piperidinone core—a novel bioisostere of the canonical hydroxyproline motif—and showed improved predicted ADME properties, including reduced efflux and better solubility. 7. Drugit’s integrated scoring system (RosettaLigand), property filters (e.g., TPSA, cLogP), and user-friendly tools empowered players to design chemically feasible, synthetically accessible molecules in a guided, iterative environment. 8. Post-game refinement included docking (Glide), torsion checks, and absolute binding free energy calculations (FEP+ and Biggin ABFE), ensuring high-confidence candidate selection for synthesis and testing. 9. The co-crystal structure revealed that the experimentally validated eutomer maintained essential hydrogen bonds and binding pocket complementarity, providing a starting point for PROTAC development with enhanced pharmacokinetics. 10. Drugit showcases a scalable and democratized approach to molecular innovation, combining AI-guided design, game-based interaction, and open-access pipelines to engage a global community in drug discovery. 💻Code: drugit.org (client download) 📜Paper: nature.com/articles/s41467-0… #drugdiscovery #crowdsourcing #foldit #computationalchemistry #citizenscience #VHL #PROTACs #moleculardesign #bioinformatics #rosetta #structurebaseddesign