8VXF

Structure of Casein kinase I isoform delta (CK1d) complexed with inhibitor 15

これはPDB形式変換不可エントリーです。

8VXF の概要

• エントリーDOI: 10.2210/pdb8vxf/pdb
• 分子名称: Casein kinase I isoform delta, (2P,3P,8S)-2-(5-fluoropyridin-2-yl)-6,6-dimethyl-3-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, ... (4 entities in total)
• 機能のキーワード: ck1d, kinase, transferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70311.07

構造登録者

Thompson, A.A.,Milligan, C.M.,Sharma, S. (登録日: 2024-02-04, 公開日: 2024-05-08, 最終更新日: 2024-11-20)

主引用文献

McCarver, S.,Hanna, L.,Samant, A.,Thompson, A.A.,Seierstad, M.,Saha, A.,Wu, D.,Lord, B.,Sutton, S.W.,Shah, V.,Milligan, C.M.,Wennerholm, M.,Shelton, J.,Lebold, T.P.,Shireman, B.T.
Structure-Based Optimization of Selective and Brain Penetrant CK1 delta Inhibitors for the Treatment of Circadian Disruptions.
Acs Med.Chem.Lett., 15:486-492, 2024

PubMed Abstract: 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 autoradiography are described for advanced analogs.

PubMed: 38628796
DOI: 10.1021/acsmedchemlett.3c00523

実験手法

X-RAY DIFFRACTION (2.28 Å)