Structure-Based Discovery of New Antagonist and Biased Agonist Chemotypes for the Kappa Opioid Receptor.

The ongoing epidemics of opioid overdose raises an urgent need for effective antiaddiction therapies and addiction-free painkillers. The κ-opioid receptor (KOR) has emerged as a promising target for both indications, raising demand for new chemotypes of KOR antagonists as well as G-protein-biased agonists. We employed the crystal structure of the KOR-JDTic complex and ligand-optimized structural templates to perform virtual screening of available compound libraries for new KOR ligands. The prospective virtual screening campaign yielded a high 32% hit rate, identifying novel fragment-like and lead-like chemotypes of KOR ligands. A round of optimization resulted in 11 new submicromolar KOR binders (best Ki = 90 nM). Functional assessment confirmed at least two compounds as potent KOR antagonists, while compound 81 was identified as a potent Gi biased agonist for KOR with minimal β-arrestin recruitment. These results support virtual screening as an effective tool for discovery of new lead chemotypes with therapeutically relevant functional profiles.