DNA-programmed assembly, characterization, and selection of small molecule libraries

ORGN 673

Edward M. Driggers, edriggers@ensemblediscovery.com, Frank Favaloro, Xiaoyu Li, Guodong Li, Ben Benton, Andrew Fraley, Josh Bittker, Arthur Morales, Scott Harbeson, and Jim Coull. Ensemble Discovery, 99 Erie St., Cambridge, MA 02139
DNA-programmed chemistry provides the foundation of an integrated platform for synthesis and identification of compounds with desired functional properties. We present a description of the integrated system, with results from the synthesis, characterization, and selection of drug-like compound libraries. Synthetic oligonucleotides are designed to program the stepwise combinatorial assembly of complex (>10e3) small molecule libraries in a single pot. At each synthetic step, the full library mixture is characterized by high-resolution time-of-flight LCMS, enabling the highly parallel synthesis to be tracked at a level comparable to single-reactions. Following assembly, each compound remains attached to the unique DNA strand which programmed its synthesis, enabling functional evaluation of the library as a mixture in microliter-scale solution-phase binding assays. High throughput hybridization and sequencing allows analysis of a broad dynamic range of binders, directly providing structure-activity information in selection experiments. Finally, we discuss unique methods to direct DNA-programmed libraries toward specific molecular targets.