Fidelity by design: Yoctoreactor and binder trap enrichment for small-molecule DNA-encoded libraries and drug discovery

•Efficient hit discovery process against challenging targets.•Discovery of potent hits to enzymes and protein–protein interaction targets.•Synthesis of multi-million member DNA-encoded small-molecule libraries using a DNA junction.•Libraries synthesized via Yoctoreactor technology ensure high fidelity.•Screening in solution by binder trap enrichment ensures low false-positive rate.

DNA-encoded small-molecule library (DEL) technology allows vast drug-like small molecule libraries to be efficiently synthesized in a combinatorial fashion and screened in a single tube method for binding, with an assay readout empowered by advances in next generation sequencing technology. This approach has increasingly been applied as a viable technology for the identification of small-molecule modulators to protein targets and as precursors to drugs in the past decade. Several strategies for producing and for screening DELs have been devised by both academic and industrial institutions. This review highlights some of the most significant and recent strategies along with important results. A special focus on the production of high fidelity DEL technologies with the ability to eliminate screening noise and false positives is included: using a DNA junction called the Yoctoreactor, building blocks (BBs) are spatially confined at the center of the junction facilitating both the chemical reaction between BBs and encoding of the synthetic route. A screening method, known as binder trap enrichment, permits DELs to be screened robustly in a homogeneous manner delivering clean data sets and potent hits for even the most challenging targets.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (221 K)Download as PowerPoint slide