Medicinal chemistry articles from across Nature Portfolio

Iontronic drug delivery is limited to small, charged molecules. Here the authors couple iontronic transport with bio-orthogonal click-to-release chemistry to unlock electrically controlled activation of drugs and proteins beyond size and charge limits.

Disulfide tethering screening is applied to address the challenge of targeting oncogenic KRAS, historically deemed undruggable due to its high nucleotide affinity and perceived lack of binding sites. Here, the authors developed a disulfide library and a set of 83 cysteine KRAS mutants to perform tethering screens towards the oncogenic KRAS, while describing the discovery of fragment-binding pockets in KRAS G12D, identified by this screening approach.

The PI3K/AKT/mTOR pathway represents an attractive drug target, but only a limited number of compounds have gained US Food and Drug Administration approval. This Perspective assesses existing class I PI3K/AKT/mTOR pathway inhibitors, highlighting lessons learned and ongoing drug development challenges. Emerging novel classes of pathway modulators, beyond the classical reversible ATP-competitive inhibitors, are focused upon.

Targeted Protein Degradation (TPD) relies on the binding of specific targets and E3 ubiquitin-ligases to promote ubiquitination and degradation of targets by the proteasome. Here, by designing chimeras that bind the proteasome-associated factor Usp14, the authors present a generalizable TPD approach based on proteasome-dependent and E3 ligase-independent small-molecule compounds.

Tetrahydroisoquinoline scaffolds are crucial in natural products and pharmaceuticals due to their diverse biological activities, yet synthetic pathways for their polycyclic forms are limited. Here, the authors present a metal-free, Vilsmeier-reagent promoted decarbonylative cyclization method, yielding derivatives with notable antitumor activity.

This work develops DJX-A-KM, a small-molecule KRASG12C degrader that recruits E3 ligase FBXO28 via dual covalent binding, inducing potent degradation. This strategy can possibly be extended to pan-KRAS degraders against a broader spectrum of KRAS mutations.

Small molecules that drive ‘neo-protein–protein interactions’ have emerged as an exciting avenue for pharmacological manipulation of protein function. A new entrant in this field inhibits oligomeric proteins by sequestering them into insoluble aggregates.

In 2025, peptide research saw the convergence of chemical synthesis and computational modelling. Advances in artificial intelligence-guided design and new macrocyclic and covalent frameworks expanded structural creativity, transforming peptides into programmable molecules with functions beyond traditional design.

Most bacteria cannot be grown in the laboratory, which means that their genetic diversity is hidden to traditional culture-based studies. We combined a new DNA extraction method, long-read sequencing, bioinformatics and chemical synthesis to access the genetic diversity of uncultured soil bacteria and abiotically decode it to discover bioactive small molecules.

The next major challenge for artificial intelligence in drug development lies in proving its value in real-world settings. A new technology not only supports the generation of novel chemical entities but also accelerates a range of real-world molecular design tasks.