1674-Ligand Optimization in Drug Discovery

Paper Talk · Oct 14, 2026 · 22m

Ligand optimization remains a fundamental yet inefficient step in early drug discovery, largely due to a lack of baseline expectations for random modifications. To establish this missing background, researchers systematically tested 257 single-atom analogues derived from 18 parent molecules across six biological targets, intentionally avoiding design biases. The experiments revealed that 11.3% of these minor structural tweaks unexpectedly improved target potency by tenfold or more, with methyl and chlorine substitutions yielding the highest success rates. However, these potency gains…