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 Gibiased 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.
Department of Biological Sciences and Department of Chemistry, Bridge Institute, University of Southern California , Los Angeles, California 90089, United States.
Zhong
Z
Zheng
Xi-Ping
XP
Huang
Thomas J
TJ
Mangano
Rodger
R
Zou
Xin
X
Chen
Department of Biological Sciences and Department of Chemistry, Bridge Institute, University of Southern California , Los Angeles, California 90089, United States.
Saheem A
SA
Zaidi
Bryan L
BL
Roth
Department of Biological Sciences and Department of Chemistry, Bridge Institute, University of Southern California , Los Angeles, California 90089, United States.
Raymond C
RC
Stevens
Department of Biological Sciences and Department of Chemistry, Bridge Institute, University of Southern California , Los Angeles, California 90089, United States.
Vsevolod
0000-0003-3883-4505
V
Katritch
D000818:Animals; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D011446:Prospective Studies; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa