Here, we demonstrate the feasibility of crowd-sourced small molecule design. Given an appropriate starting structure and objectives, game playersincluding those with limited medicinal chemistry experiencecan design compounds which not only successfully meet compound quality criteria, but also bind well to a protein target of interest. Due to the provided objective criteria as well as the post-game property filtering, compound 1 is characterized by its improved predicted physicochemical properties, specifically with respect to the lower TPSA, higher intrinsic permeability, and lower efflux ratio comparised to ligand 10 (Table ). The identified novel hydroxypiperidinone core as a bioisosteric replacement for the classical hydroxyproline motif provides an interesting starting point for further structural extension by virtue of its chemical nature, though the undecorated 1,3-dicarbonyl motif in turn also presents a configurationally labile stereocenter in its current state. The biophysical affinity of 1 (KD = 258 ± 8 µM) toward the protein versus the peptide-like starting molecule is significantly lower, however it should be noted that this affinity is averaged due to the diastereomeric mixture.