Large-Scale Structure-Based Virtual Screening Identifies Diverse KNa1.1 (KCNT1) Potassium Channel Inhibitors

Severe drug-resistant childhood epilepsy is caused by KCNT1 gain-of-function genetic variants, resulting in increased K Na 1.1 channel activity. KCNT1 -associated epilepsy is thought to affect around 1 in 300,000 births worldwide. Current treatment for KCNT1 epilepsy only provides mild symptomatic relief and uses a cocktail of experimental medications which must be personalised for the individual and are often poorly tolerated. Critically, with many patients, no therapeutic benefit is achieved. We sought to address this by using large-scale virtual screening to accelerate the development of a molecule which binds directly to KCNT1 to supress overactivity. We purchased a total of 71 compounds and using a combination of fluorescent thallium flux assays and patch clamp electrophysiology, identified a series of eight structurally diverse, novel inhibitors of the K Na 1.1 channel with potency in the low micromolar range. These provide potential starting points for further development of drugs to treat KCNT1 -associated epilepsy. • We have discovered a range of structurally distinct inhibitors of the KCNT1 ion channel using large-scale virtual screening. • These compound exhibit selectivity for the KCNT1 channel over other related ion channels. • These compounds could provide starting points for developing new treatments for KCNT1 related Epilepsy.