Small-molecule discovery from DNA-encoded chemical libraries

Researchers seeking to improve the efficiency and cost effectiveness of the bioactive small-molecule discovery process have recently embraced selection-based approaches, which in principle offer much higher throughput and simpler infrastructure requirements compared with traditional small-molecule screening methods. Since selection methods benefit greatly from an information-encoding molecule that can be readily amplified and decoded, several academic and industrial groups have turned to DNA as the basis for library encoding and, in some cases, library synthesis. The resulting DNA-encoded synthetic small-molecule libraries, integrated with the high sensitivity of PCR and the recent development of ultra high-throughput DNA sequencing technology, can be evaluated very rapidly for binding or bond formation with a target of interest while consuming minimal quantities of material and requiring only modest investments of time and equipment. In this tutorial review we describe the development of two classes of approaches for encoding chemical structures and reactivity with DNA: DNA-recorded library synthesis, in which encoding and library synthesis take place separately, and DNA-directed library synthesis, in which DNA both encodes and templates library synthesis. We also describe in vitro selection methods used to evaluate DNA-encoded libraries and summarize successful applications of these approaches to the discovery of bioactive small molecules and novel chemical reactivity.Chemistry and Chemical Biolog

Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery

The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with current compound collections is proving increasingly difficult. Encoded library technologies enable the rapid exploration of large chemical space for the identification of ligands for such targets. These binders facilitate drug discovery projects both as tools for target validation, structural elucidation and assay development as well as starting points for medicinal chemistry. Novartis internalized two complementing encoded library platforms to accelerate the initiation of its drug discovery programs. For the identification of low-molecular weight ligands, we apply DNA-encoded libraries. In addition, encoded peptide libraries are employed to identify cyclic peptides. This review discusses how we apply these two platforms in our research and why we consider it beneficial to run both pipelines in-house

Encoded Self-Assembling Chemical Libraries

The display of chemical moieties at the extremity of synthetic oligonucleotides allows the self-assembly of large chemical libraries in which every chemical moiety is associated to a unique DNA sequence, serving as an 'identification bar code'. In this article, we describe the principles, the potential, and the challenges of this novel technology, which promises to facilitate the isolation of high-affinity binders to protein targets of biological and pharmaceutical interest

Interaction-Dependent PCR: Identification of Ligand−Target Pairs from Libraries of Ligands and Libraries of Targets in a Single Solution-Phase Experiment

Interaction-dependent PCR (IDPCR) is a solution-phase method to identify binding partners from combined libraries of small-molecule ligands and targets in a single experiment. Binding between DNA-linked targets and DNA-linked ligands induces formation of an extendable duplex. Extension links codes that identify the ligand and target into one selectively amplifiable DNA molecule. In a model selection, IDPCR resulted in the enrichment of DNA encoding all five known protein−ligand pairs out of 67 599 possible sequences