A simple tweak to a tool for making macrocyclic compounds could help increase the diversity of DNA-encoded libraries used by drug developers to rapidly screen and identify promising drug candidates (Bioconjugate Chem. 2017, DOI: 10.1021/acs.bioconjchem.7b00292). Building such libraries involves facilitating reactions between small molecules tagged with short, unique DNA sequences to create myriad products, which are then tagged with additional unique DNA sequences. The DNA serves as a sort of bar code to identify the compounds in a library that successfully bind to a particular drug target. However, these libraries generally have not been able to include ring compounds in the drug screening because transition-metal catalysts, essential for ring-closing reactions, can bind to charged DNA backbones and cause the strands to fall apart. Now, a team led by Xiaojie Lu and Lijun Fan of GlaxoSmithKline has found that by protecting the DNA tags with magnesium ions, they can produce a variety of DNA-encoded heterocycles and macrocycles using ruthenium-catalyzed ring-closing metathesis. The team hypothesizes that because the magnesium ions occupy all the DNA’s binding sites, the ruthenium catalyst is forced to react with the substrates instead of the DNA.