Chemical libraries articles from across Nature Portfolio

Isofagomine (IFG) and its analogs have promising glycosidase inhibitory activities, however, a flexible synthetic strategy toward C5a-functionalized IFGs remains to be achieved. Here, the authors show a practical synthesis of C5a-S and R-aminomethyl IFG derivatives via diastereoselective addition of cyanide to cyclic nitrone, and the synthesized derivatives are subsequently assessed for their efficacy as GCase stabilizers.

Polyketide macrolides are of interest for drug discovery but their inherent structural and stereochemical complexity hinders the exploration of related regions of chemical space more broadly. Here, the authors designed in silico and synthesized a library of tetrahydrofuran-containing polyketide macrolides, and screened them against a panel of biological assays, identifying biologically active library members.

Design strategies that possess both biological relevance and structural diversity may lead to compound collections that are enriched in diverse bioactivities. Now a diverse pseudo-natural product design principle has been established to efficiently explore biologically relevant chemical space. Through dearomatization reactions, a compound collection enriched in both structural and biological diversity was rapidly generated.

Amines and carboxylic acids are abundant chemical feedstocks, however, the current reaction space of those two building blocks is focused on amide coupling. Here, the authors extensively explore the amine–acid reaction space via systematic reaction enumeration using graph editing and demonstrate its utility in retrosynthetic analysis as well as late-stage diversification.

Stapled α-helical peptides are promising for targeting challenging targets such as transcription factors, but achieving sufficient cell permeability while avoiding off-target cleavage is difficult. Here, the authors present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects based on comprehensive investigations of their properties.

Cyclic peptides show promise for modulating difficult disease targets; however, they often cannot be administered orally. The authors developed a method to synthesize and screen large libraries of small cyclic peptides while enabling the simultaneous interrogation of activity and permeability. This approach was applied to the disease target thrombin to discover peptides with high affinity, stability and oral bioavailability of up to 18% in rats.

The rules for designing cyclic peptides with drug-like properties are unclear. Two studies now show how cyclic peptide libraries can be created to optimize properties such as cell permeability before screening for binding activity. The approach has led to a macrocyclic peptide inhibitor for KRAS that has reached clinical trials.

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.

Late-stage modification of peptides with photoactivatable groups often weakens their binding interaction with target proteins. Now, this challenge has been addressed using large libraries of cyclic peptides with photocrosslinkers incorporated prior to screening.

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.

Modern drug discovery relies upon intelligent exploration of ‘in stock’ and ‘on demand’ virtual libraries of compounds. A comparative analysis highlights the explosive expansion of accessible chemical space and also reveals challenges and opportunities arising for computational drug discovery.