The Influence of Single-Stranded or Double-Stranded DNA Tags on Ligand Binding Affinity in DNA-Encoded Libraries.

DNA-encoded libraries have become widely used in drug discovery, and several different setups to link chemical compounds to DNA have been employed in the field, including single-stranded and double-stranded DNA tags as well as a variety of linker chemistries. In our previous study, we observed distinct differences in binding affinities between ligands coupled either to single-stranded or double-stranded DNA; however, the molecular basis for these differences remained unclear. Here, we present a native ion mobility mass spectrometry approach that incorporates gas- and solution-phase activation techniques to systematically investigate these differences, specifically the impact of DNA tags on binding performance in protein-ligand interactions.

Native Mass Spectrometry Facilitates Hit Validation in DNA-Encoded Library Technology.

DNA-encoded Library (DEL) Technology has become a workhorse of drug development, is widely employed in an industrial and academic setting, and an increasing number of drugs developed by DEL technology have entered clinical stage development. While up to billions of compounds can be screened simultaneously in affinity-based selections, the validation and characterization of individual hits discovered from DEL selections is a substantial bottleneck since it can be cumbersome and time-consuming. Here, we describe the use of native mass spectrometry for the speedy hit validation of On-DNA compounds.

Flexibility-tuning of dual-display DNA-encoded chemical libraries facilitates cyclic peptide ligand discovery.

Cyclic peptides constitute an important drug modality since they offer significant advantages over small molecules and macromolecules. However, access to diverse chemical sets of cyclic peptides is difficult on a large library scale. DNA-encoded Chemical Libraries (DELs) provide a suitable tool to obtain large chemical diversity, but cyclic DELs made by standard DEL implementation cannot efficiently explore their conformational diversity.

Advancing small-molecule drug discovery by encoded dual-display technologies.

DNA-encoded chemical library technology (DECL or DEL) has become an important pillar for small-molecule drug discovery. The technology rapidly identifies small-molecule hits for relevant target proteins at low cost and with a high success rate, including ligands for targeted protein degradation (TPD). More recently, the setup of DNA- or peptide nucleic acid (PNA)-encoded chemical libraries based on the simultaneous display of ligand pairs, termed dual-display, allows for more sophisticated applications which will be reviewed herein.

Universal encoding of next generation DNA-encoded chemical libraries.

DNA-encoded chemical libraries (DELs) are useful tools for the discovery of small molecule ligands to protein targets of pharmaceutical interest. Compared with single-pharmacophore DELs, dual-pharmacophore DELs simultaneously display two chemical moieties on both DNA strands, and allow for the construction of highly diverse and pure libraries, with a potential for targeting larger protein surfaces. Although methods for the encoding of simple, fragment-like dual-display libraries have been established, more complex libraries require a different encoding strategy.