Development of a random background to understand ligand optimization.

11.3% of randomly modified ligands across six targets improved potency tenfold or more, revealing a surprising baseline for ligand optimization success.

• Why it matters: Understanding the likelihood of significant improvements in ligand potency is crucial for evaluating drug discovery efforts and avoiding overestimation of optimization success.
• What they did: The study systematically introduced single-atom changes to 18 lead molecules, synthesizing 257 compounds to measure their effects on potency and pharmacokinetics.
• The result: Findings suggest that while substantial potency gains are possible through random modifications, they often come with worse pharmacokinetics, highlighting the challenges in translating in vitro improvements to in vivo efficacy.