Combinatorial libraries articles from across Nature Portfolio

Riebesell et al. introduce Matbench Discovery, a framework to compare machine learning models used to identify stable crystals. Out of several architectures, they find that universal interatomic potentials perform best in the competition.

C–H functionalization is a key reaction in organic synthesis. Now a selenoxide reagent has been developed for the formation of arylselenonium salts via C–H functionalization of DNA conjugates with high selectivity. The arylselenonium salts participate in various transformations to forge new C–C and C–X bonds.

This protocol describes solid-phase DNA-encoded library synthesis suitable for various high-throughput screening applications. The libraries are constructed using consecutive on-bead chemical synthesis and DNA encoding ligations, resulting in decodable library beads.

A quantitative fluorescence-activated cell sorting method for generating fully human conformational antibodies against amyloid aggregates associated with neurodegenerative disorders—without the need for immunization—has now been developed. Engineered antibodies obtained using this approach show properties rivaling those of clinical-stage antibodies specific for tau and α-synuclein amyloid aggregates.

Lyme borreliosis is challenging to diagnose, particularly in its early stages. Aptamers targeting CspZ from Borrelia, selected through cross-over SELEX, bind both the recombinant protein and bacteria, demonstrating potential for enhanced diagnostics.

Cyclic peptides offer access to therapeutics with properties that sit between biologics and small molecules. A 2009 study reported the design, construction and selection of a phage-encoded bicyclic peptide library that used a chemical linker for cyclization. This and other advanced display technologies have accelerated the de novo discovery of functional cyclic peptides.

A protein-templated selection approach has been developed for the discovery of full ligands from dual-pharmacophore DNA-encoded libraries by incorporating fragment linking into the selection process. The performance of this method was demonstrated with selections against protein–protein interaction and protein–DNA interaction targets, through which potent and selective inhibitors were identified.

Cyclic peptides can bind challenging disease targets, but their oral application is hindered by digestion and absorption issues. We developed a versatile method for the synthesis and functional screening of vast numbers of synthetic cyclic peptides and identified peptides with high inhibitory activity, stability and oral bioavailability in rats.

DNA-encoded libraries are a powerful tool to identify novel chemical inducers of proximity such as targeted protein degraders, even without a known binder for the target protein.

The most popular reactions used by medicinal chemists are often incompatible with nanoscale ultrahigh-throughput experimentation (ultraHTE). Now, a set of ultraHTE-amenable reaction conditions is reported for four of the most important transformations in drug discovery, and their generality and scalability tested on a range of complex natural products and drug candidates.

Explaining the controlled emergence and growth of molecular complexity at life’s origins is one of prebiotic chemistry’s grand challenges. Now, it has been shown that we can observe how the self-organization of a complex carbohydrate network can be modulated by its environment.