qHTS to Identify Small Molecule GUS Inhibitors

National Center For Advancing Translational Sciences

Investigators

Linked publications & trials

Abstract

As such, this project aims to screen the chemical libraries at NCATS against a novel, disease relevant microbiome target to identify promising hits that can be further developed and optimized into tomorrows symbiotic drugs. After establishing the collaborative framework for this project, a high-throughput assay against a key ortholog from the GUSsome was optimized, miniaturized, and implemented to identify at least 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. Four different chemical series were followed up with medicinal chemistry SAR-driven optimization. A key piperazine moiety seems essential for activity and may play a role in forming an adduct with the enzyme substate. A contract with XTAL (Schrodinger) has been placed to determine X-ray studies to guide structure-based drug design. Lead compounds from three series are also being characterized at Symberix in RgGUS (closely related to H11G11, the GUS that used in the screen) and in cell-based assays.