Volume 14 Issue 12, December 2018

Current drug discovery efforts focus on proteins because of their ability to form stable, structured pockets. A recent study demonstrates that targeting stable, structured bioactive RNA motifs, such as autocatalytic introns, may provide a novel method of expanding druggability and selectivity.

Terpenoids are assembled from five-carbon (C5) units, which limits the available scaffold chemical space for the discovery of bioactive molecules. A combination of enzyme and metabolic engineering now enables biosynthesis of a plethora of non-natural C11 terpenoids.

Scientists have combined functional and computational analysis to predict the substrate specificity of a family of glycosyltransferases from Arabidopsis thaliana, creating a tool that enables researchers to classify the donor and acceptor specificity of glycosyltransferase enzymes.

High-throughput screening followed by an examination of structure–activity relationship-based optimization resulted in the identification of potent small-molecule inhibitors of group IIB intron splicing in fungal organisms.

The HIV protease inhibitor ritonavir targets the calcium-inducing domain (CID) of CD95 to block interactions with PLCγ1. Peptidomimetics targeting the CD95 CID prevents accumulation of inflammatory Th17 cells observed in systemic lupus erythematosus.

Yeast engineered to produce the six-carbon terpene building block 2-methyl-geranyl diphosphate, coupled with terpene synthases engineered to accept this noncanonical substrate, enables the biosynthesis of a collection of new C11 terpenoid scaffolds.

High-throughput screening and activity-based protein profiling find a selective and in vivo–active inhibitor of the membrane-associated serine hydrolase ABHD12 that alters lysophospholipid content and has immunostimulatory effects.

Bioinformatic analysis coupled to substrate-reactivity profiling for the glycosyltransferase (GT) enzyme superfamily supports the development of ‘GT-Predict’ as a tool for functional prediction of GT–substrate relationships.

The use of an allosteric drug-design method resulted in the identification of a first-in-class cellularly active SIRT6 activator that induces cell-cycle arrest in the G₀–G₁ phase, thus suppressing proliferation in human hepatocellular carcinoma cells.

Structural and biochemical analysis of propionyl-CoA synthase reveals that it forms a reaction chamber containing three active sites, which sequesters the reactive intermediate acrylyl-CoA during the conversion of 3-hydroxypropionate to propionyl-CoA.

The freshwater microcrustacean Daphnia pulex forms defensive neckteeth in response to a collection of chemical cues (the kairomone), now identified as certain fatty acids conjugated to glutamine, released during digestion by its predator Chaoborus.

An inhibitor of the YEATS domain was developed by targeting a unique π-π-π stacking in the YEATS–Kcr recognition. An ENL YEATS-selective inhibitor, XL-13m, helps probe the YEATS-dependent role of ENL in the leukemogenic transcription program.

A structural study supported by molecular dynamics simulations describes the basis of receptor-subtype selectivity of a small-molecule antagonist of the human muscarinic M₂ receptor.