Fig. 2.

The PYR1 binding pocket can be mutated to sense small molecules of broad chemical scope. (A) Summary of ligands sensed by receptors isolated from a 2,726-member small molecule library screen. The hits obtained include FDA-approved molecules, natural products, agrochemicals, and a collection of research ligands (see Dataset S1 for the ligands screened). (B) The molecules sensed by PYR1-derived sensors are structurally diverse. The heatmap shows hierarchical clustering based on the pairwise chemical similarities of the 181 hit molecules. Pairwise ligand-similarity, measured using Tanimoto scores calculated from atom-pair descriptors in ChemmineR (21), is shown by the heatmap (blue = identical). Selected clusters of similar ligands are highlighted. (C). Selected chemical ligands from each cluster identified in part B. (D) PYR1-derived receptors sense drug-like molecules. Comparisons of the physicochemical properties of ligand hits (n = 181) and the nonhits (n = 2,545). Molecular weight (MW), computationally calculated octanol–water partition coefficient (cLogP), topological polar surface area, and a quantitative estimate of drug-likeness (24) values were extracted from ChEMBL (23). The median for each population is shown, along with the p-value from a two-sided Wilcoxon rank-sum test. R code is available at https://github.com/cutlersr/PYR1_sensor_screen.