Researchers created a random background for ligand optimization in drug discovery. They modified 18 lead molecules across six targets with single-atom changes. 257 compounds were synthesized as a result. 11.3% of these random changes improved potency by tenfold or more. These improved analogues typically had worse in vitro pharmacokinetics. Some analogues still showed stronger in vivo potency despite poorer exposure. The study reveals a frustrated landscape for ligand optimization. It offers a simple strategy to establish a background expectation. The work also quantifies challenges in moving beyond in vitro potency.
What changed
No established random background existed for comparing ligand optimization improvements.
What it unlocks
Establishing a baseline expectation for how often random small changes improve ligand potency.
- 18 lead molecules across six targets
- 257 compounds synthesized
- 11.3% improved potency tenfold or more
Sources