Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 52, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2021.128375
Keywords
Glycogen synthase kinase3 beta; Structure-based virtual screening; Protein kinase assay; Molecular dynamics simulation
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Funding
- Central University of Rajasthan
- ADMET Predictor software facilities, Department of Science and Technology, Rajasthan [L7 (3) ST/RD/2016/2616]
- Asinex Corporation
- Council for Scientific and Industrial Research, India, for the Senior Research Fellowship [09/1131(0004)/2016-EMR-I, 09/1131(0026)/2019-EMR-I]
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The study identified new GSK-3 beta inhibitors with potential in Alzheimer's disease pathology, among which ZINC09036109 showed promising selectivity and strong binding affinity with GSK-3 beta.
GSK-3 beta directly phosphorylate tubulin binding site of tau protein, indicating its importance in tau aggregation and, therefore, in Alzheimer's disease pathology. New GSK-3 beta inhibitors were identified using a structure-based screening, ADMET analysis. These studies revealed that ZINC09036109, ZINC72371723, ZINC72371725, and ZINC01373165 approached optimal ADMET properties along with good MM-GBSA dG binding. Protein kinase assays of these compounds against eight disease-relevant kinases were performed. During disease-relevant kinase profiling, ZINC09036109 ((E)-2-((3,4-dimethylphenyl)imino)-5-(3-methoxy-4-(naphthalen-2-ylmethoxy)benzyl) thiazolidin-4-one) emerged as a selective GSK-3 beta inhibitor with more than 10-fold selectivity over other disease-relevant kinases. Molecular dynamics study of ZINC09036109 molecule revealed interactions with Ile62, Phe67, Val135, Leu188, Asp200 amino acid residues of the binding site of GSK-3 beta, which were highly comparable to the co-crystallized molecule and hence validating comparative better activity of this compound compared to overall screened molecules.
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