Wesley Cochrane; Marie Lynne Malone; Vuong Q Dang; Valerie J. Cavett; Alexander L. Satz; Brian M Paegel
ACS Comb. Sci., 2019, 21, 5, 425-435
https://doi.org/10.1021/acscombsci.9b00037

Abstract

Robotic high-throughput compound screening (HTS) and, increasingly, DNA-encoded library (DEL) screening are driving bioactive chemical matter discovery in the post-genome 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 IC50s 4–10 µM). 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.