Encoded Library Synthesis Using Chemical Ligation and the Discovery of Seh Inhibitors from a 334-Million Member Library

A chemical ligation method for construction of DNA-encoded small-molecule libraries has been developed. Taking advantage of the ability of the Klenow fragment of DNA polymerase to accept templates with triazole linkages in place of phosphodiesters, we have designed a strategy for chemically ligating oligonucleotide tags using cycloaddition chemistry. We have utilized this strategy in the construction and selection of a small molecule library and successfully identified inhibitors of the enzyme soluble epoxide hydrolase.