This Perspective discusses the application of algorithmic methods throughout the preclinical phases of drug discovery to accelerate initial hit discovery, mechanism-of-action elucidation and chemical property optimization.

RAS proteins, central drivers of cancer, appeared ‘undruggable’ for almost 30 years. Here we provide a personal perspective on the effort leading to our initial report of KRAS^G12C inhibitors in 2013, and the decade of discoveries that followed.

Boron is a common element found in various minerals; however, it is not used in life-creating machinery in nature. In a new study, boron enzymes have been created by introducing a boronic acid-containing non-canonical amino acid into an artificial enzyme scaffold. Further development via directed evolution enabled the selection of new-to-nature stereoselective chemistry.

The inaugural CRISPR-based drug Casgevy has been approved by several medical agencies, with other CRISPR-based therapies currently in clinical trials. Although there are technological hurdles to overcome, chemical biology has a vital role in developing recent breakthroughs in base editing, prime editing and epigenetic editing into future treatments.

A tRNA modification, named 2-aminovaleramididine (ava²C), has been discovered in plant organelles and bacteria. Structural analysis shows specific codon recognition by this modification, highlighting the evolutionary diversity of the essential tRNA modifications.

Li, Cheng, Yu and colleagues have discovered a Cas13j family, including the compact and highly efficient LepCas13j (529 aa) and ChiCas13j (424 aa), with promising applications in RNA editing in vivo.

Development of a paralog-hopping approach leveraging chemical proteomic data on covalently liganded cysteines revealed an allosteric pocket shared by cysteine-containing and cysteine-less paralogous cyclin E proteins.

A modular multicellular system has been created by mixing and matching discrete engineered bacterial cells in an artificial neural network-type architecture. The system is capable of solving multiple computational decision problems like identifying a number as prime and a letter as a vowel.

Naturally occurring peptide–nucleobase hybrids are rare. Here Pei et al. report the discovery and biosynthetic studies of the first peptide–nucleobase hybrid catalyzed by an RRE–YcaO–dehydrogenase complex from a RiPP pathway, and show the biotransformation in a substrate-assisted manner.

The incorporation of nitrogen in steroidal glycoalkaloids is hypothesized to occur through a transamination reaction. Here, the authors show that GLYCOALKALOID METABOLISM12 appears to evolve from the canonical γ-aminobutyric acid transaminases and directs the biosynthesis of nitrogen-containing steroidal metabolites in Solanum plants.

Orally bioavailable, high molecular weight macrocyclic peptides that inhibit difficult-to-drug protein–protein interactions are of high therapeutic value, and rules for their design were proposed recently. Here, we emphasize the danger of rules that provide a false impression of the lipophilicity required of a clinical candidate.