Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions.
Stefan J McCarverLuke HannaAndrew SamantAaron A ThompsonMark J SeierstadArjun SahaDongpei WuBrian LordSteven W SuttonVishal ShahCynthia M MilliganMichelle WennerholmJonathan SheltonTerry P LeboldBrock T ShiremanPublished in: ACS medicinal chemistry letters (2024)
Neuropsychiatric disorders such as major depressive disorders and schizophrenia are often associated with disruptions to the normal 24 h sleep wake cycle. Casein kinase 1 (CK1δ) is an integral part of the molecular machinery that regulates circadian rhythms. Starting from a cluster of bicyclic pyrazoles identified from a virtual screening effort, we utilized structure-based drug design to identify and reinforce a unique "hinge-flip" binding mode that provides a high degree of selectivity for CK1δ versus the kinome. Pharmacokinetics, brain exposure, and target engagement as measured by ex vivo autoradiography are described for advanced analogs.
Keyphrases
- protein kinase
- bipolar disorder
- resting state
- white matter
- functional connectivity
- cerebral ischemia
- physical activity
- social media
- sleep quality
- multiple sclerosis
- molecular docking
- stress induced
- single molecule
- brain injury
- adverse drug
- replacement therapy
- binding protein
- molecular dynamics simulations
- subarachnoid hemorrhage