Journal
ACS COMBINATORIAL SCIENCE
Volume 21, Issue 5, Pages 425-435Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscombsci.9b00037
Keywords
DNA-encoded library; microfluidics; droplet; OBOC; drug discovery
Funding
- National Institute of Health [R01GM120491]
- National Science Foundation CAREER award [1255250]
- Farris Foundation Graduate Research Fellowship Award
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1255250] Funding Source: National Science Foundation
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Robotic high-throughput compound screening (HTS) and, increasingly, DNA-encoded library (DEL) screening are driving bioactive chemical matter discovery in the postgenomic era. HTS enables activity-based investigation of highly complex targets using static compound libraries. Conversely, DEL grants efficient access to novel chemical diversity, although screening is limited to affinity-based selections. Here, we describe an integrated droplet-based microfluidic circuit that directly screens solid-phase DELs for activity. An example screen of a 67 100-member library for inhibitors of the phosphodiesterase autotaxin yielded 35 high-priority structures for nanomole-scale synthesis and validation (20 active), guiding candidate selection for synthesis at scale (5/5 compounds with IC50 values of 4-10 mu M). We further compared activity-based hits with those of an analogous affinity-based DEL selection. This miniaturized screening platform paves the way toward applying DELs to more complex targets (signaling pathways, cellular response) and represents a distributable approach to small molecule discovery.
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