High throughput crystallographic compound screening

Division Of Basic Sciences - Nci

Investigators

Abstract

During FY 2025 we brought the fragment screening infrastructure online. This required the integration of several liquid handlers that provide reproducible crystallization conditions in scale as well as delivery of libraries of small molecules as well as the development of data and metadata handling for tracking of hits. We are collecting our first datasets using a ~950 fragment library and a well-behaved crystal system from a bacterial protein as proof of principle. We are also collecting the first dataset on a prolyl-endopeptidase to expand on the chemistry of potential inhibitors. We are expanding these high-throughput crystallography capabilities to asses hits from other assays obtained from the Molecular Targets Program. With these novel approaches, we are blurring the barriers between screening techniques and harnessing structural information early on to drive structure-activity relationship determinations. This part of the project is focusing on the inhibition of a protein from a multi-drug-resistant fungus that poses significant life threats to immunosuppressed individuals.