Fragment-based drug discovery (FBDD) is widely used in the pharmaceutical industry to provide novel hits for developing new therapeutics. It allows a more efficient scanning of chemical space with a higher hit rate compared to high-throughput screening, and this has important outcomes in early drug discovery.<br/>Protein X-ray crystallography (PX) is the gold standard for experimentally defining exact binding of a ligand to asses directly target engagement. Absence of crystal structures of target-ligand complexes is a significant impediment to medicinal chemistry optimization of hits. Conventional crystallography is inefficient for screening a large fragment or scaffold library due to expense and effort. Complementary experimental techniques, such as SPR, NMR or TSA are often used to prescreen for ligands that bind, while crystallography is used in a second step to determine the exact binding of each ligand.<br/>With foundational expertise in structural biology, structural genomics and HT PX, we have developed novel methods for hit generation in early drug discovery. Our platform for ultrahigh-throughput crystallography-based fragment and scaffold library screening (cryo or room temperature structures) accelerates hit generation and hit-to-lead development by directly providing 3D structures of target-bound ligands, potentially leading to ~5-7x reduction in early drug discovery effort while generating IP in the form of identifying binding sites and protein-ligand interactions.  This provides unprecedented experimental route to high quality, high reliability and high value results simultaneously: identification and assessment of target engagement by ligand binding sites and poses; target ligandability; and differentiation of orthosteric and allosteric sites and binders. We will present results on various targets; and how it has helped to spur growth of new therapeutics discovery and development, resulting in advancing from hits to functional leads in several weeks.

Early drug discovery hit generation by ultrahigh-throughput crystallography-based screening

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.