qHTS to Identify Small Molecule GUS Inhibitors

National Center For Advancing Translational Sciences

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Abstract

This project aims to screen the chemical libraries against a novel, disease relevant microbiome target to identify promising hits that can be further developed and optimized into symbiotic drugs. The project team optimized, miniaturized, and implemented a high-throughput assay against a key ortholog from the GUSsome to identify several different chemical series as hits. Purified resynthesized and procured powders have been used for hit validation and followed by detailed characterization of hit activity against a diverse panel of bacterial GUS enzymes. Several different chemical series were followed up with medicinal chemistry SAR-driven optimization. Lead compounds are being characterized in cell-based assays. The team has additionally developed homology models for GUS and applied them to large-scale virtual screening against nearly 400,000 compounds, and several hits were found to exhibit positive inhibitory activity in a follow-up GUS biochemical assay in vitro.