In silico identification, synthesis, and in vitro pharmacological characterization of potent and selective blockers of the epilepsy-associated KCNT1 potassium channel
Lidia Carotenuto, Nunzio Iraci, Tania Ciaglia, Giorgio Belperio, Francesca Di Matteo, Ilaria Mosca, Giusy Carleo, Manuela Giovanna Basilicata, Paolo Ambrosino, Rita Turcio, Ilenio Servettini, Giacomo Pepe, Isabel Maria Gomez-Monterrey, Maria Virginia Soldovieri, Veronica Di Sarno, Pietro Campiglia, Francesco Miceli, Alessia Bertamino, Carmine Ostacolo, Maurizio Taglialatela · FENS Forum 2024
Gain-of-function variants in the Na+-regulated K+ channel KCNT1 are associated to severe, drug-resistant forms of epilepsy. Quinidine has been used as a KCNT1 blocker, both in vitro and in vivo, though with conflicting clinical outcomes.To identify novel KCNT1 blockers, in the present work an in-house library of >800 compounds underwent a virtual screening based on docking energy scores and similarity to the quinidine bound conformation in a homology model of hKCNT1. Twenty molecules were selected and further screened in vitro using a Tl+-based fluorescent assay in KCNT1-expressing CHO cell