Journal
MEDICINAL CHEMISTRY RESEARCH
Volume 31, Issue 9, Pages 1545-1557Publisher
SPRINGER BIRKHAUSER
DOI: 10.1007/s00044-022-02912-z
Keywords
Alzheimer'sdisease; Structure-based virtual screening; Glycogen synthase kinase-3 beta; Kinase inhibitory assay; Molecular dynamic simulation
Categories
Funding
- Department of Science and Technology, India [INT/FRG/DAAD/P-10/2018]
- Council of Scientific and Industrial Research, India [09/1131(0026)/19-EMR-I]
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Alzheimer's Disease is a significant disease affecting the aging population and is challenging to develop drugs due to blood-brain barrier permeation. This study performed virtual screening on a compound library and identified 10 potential compounds with favorable ADME profiles. In vitro studies revealed a compound with high GSK-3β inhibition and selectivity. Additionally, a potent and selective CK1ε inhibitor was discovered.
Alzheimer's Disease (AD) is one of the significant diseases of the aging population and affects Central Nervous System dominantly. Blood-brain-barrier permeation is a substantial complication in developing CNS drugs, and it is considered challenging with minimal success rates. Although Glycogen synthase kinase-3 beta (GSK-3 beta) is an attractive disease-modifying target for AD, there is no single GSK-3 beta inhibitor in clinical trials for AD. Here we performed structure-based virtual screening on the Chembridge CNS-Set library compounds. 10 hits were identified based on interaction, binding energy, dock score, and a potential ADME profile. These 10 chosen compounds were then investigated for in vitro kinase inhibitory activity against GSK-3 beta and other AD-related kinases. Among these, the molecule 7114202 showed 48% GSK-3 beta inhibition while showing selectivity over other AD-related kinases. Molecular dynamic simulations of apoenzyme, co-crystallized molecule, and 7114202 validated the Lys85, Val135, Leu188, Asp200 located in the active site of enzyme play a significant role in GSK-3 beta complex formation with inhibitors, and they are responsible for activity and selectivity. The in vitro studies also revealed a potent and selective Casein Kinase 1 epsilon (CK1 epsilon) inhibitor 7774767 with IC50 5.10 mu M. [GRAPHICS] .
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