“Massively parallel, single-molecule assessment of synthetic fidelity and drug-like properties in a DNA-encoded library”
Dr. Scott Lokey
Professor, Department of Chemistry and Biochemistry
Director of Chemical Screening Center
University of California Santa Cruz
Professor bio:
Scott Lokey received his Ph.D. at the University of Texas, Austin in organic chemistry under the mentorship of Dr. Brent Iverson. His graduate research centered on the synthesis of molecules that fold into protein-like shapes in water and on poly-intercalators bind DNA sequence-specifically. He did post-doctoral research at Genentech, where he worked on the synthesis of bioactive cyclic peptides, and then at Harvard Medical School on the synthesis of molecules designed to disrupt cellular processes related to motility. He joined the faculty at UCSC in 2002 in the Department of Chemistry and Biochemistry, where his research group focuses on the relationship between molecular structure and drug-like properties, especially cell permeability. Professor Lokey is also the director of the UCSC Chemical Screening Center, a high-throughput screening facility dedicated to early stage lead discovery, and is co-founder of Circle Pharma, a biotech startup focusing on the discovery of cyclic peptide inhibitors against intracellular targets.
Abstract:
DNA-encoded libraries (DELs) have emerged as a prominent drug discovery strategy, but successful translation of hits is often impeded by low-quality libraries and enrichment of poorly permeable compounds. We have developed a novel sequencing-based separation strategy called LC-seq that simultaneously evaluates synthetic fidelity and permeability-relevant lipophilicity for individual DNA-encoded library members. Using a 60,000-member macrocyclic peptide library, we mapped reaction efficiency across all synthetic cycles and identified structure-reactivity trends. The on-DNA lipophilicities for resynthesized library members correlate strongly with their off-DNA lipophilicities and passive permeability in artificial membranes and MDCK cells. This approach enables direct assessment of compound quality and drug-like properties at unprecedented scale, potentially transforming DEL-based drug discovery.
