Saturated, chiral five-membered sulfur heterocycles expand ligand space for the CaMKIIα hub domain and show good cell permeability
- Building on the thiazole ligand PTCA, the authors explored related five-membered sulfur heterocycles that bind the CaMKIIα hub domain, the high-affinity site of GHB.
- Greater saturation and chirality were introduced to diversify the scaffold while keeping physicochemical properties favorable.
- Activity depended on the presence and position of sulfur relative to the carboxylic acid, with stereoselective recognition.
- Two mid-nanomolar ligands showed good cellular permeability and were not efflux transporter substrates.
💡 Points Based on the abstract
A neat move away from flat aromatic PTCA toward saturated, chiral S-heterocycles: more sp3 character and stereo-resolved SAR suggest a real hub-pocket fit, not nonspecific acid binding. Caveat: a carboxylic acid yet good permeability is surprising. Next I'd check selectivity against other GHB-site proteins, brain exposure, and a crystal structure to rationalize why sulfur position matters.