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Article Dans Une Revue Bioorganic and Medicinal Chemistry Letters Année : 2021

Discovery of thiazolidin-4-one analogue as selective GSK-3β inhibitor through structure based virtual screening

Résumé

GSK-3β directly phosphorylate tubulin binding site of tau protein, indicating its importance in tau aggregation and, therefore, in Alzheimer's disease pathology. New GSK-3β 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-3β inhibitor with more than 10-fold selectivity over other diseaserelevant kinases. Molecular dynamics study of ZINC09036109 molecule revealed interactions with Ile62, Phe67, Val135, Leu188, Asp200 amino acid residues of the binding site of GSK-3β, 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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Dates et versions

hal-03867355 , version 1 (30-11-2022)

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Bhanwar Singh Choudhary, Pakhuri Mehta, Stéphane Bach, Sandrine Ruchaud, Thomas Robert, et al.. Discovery of thiazolidin-4-one analogue as selective GSK-3β inhibitor through structure based virtual screening. Bioorganic and Medicinal Chemistry Letters, 2021, 52, ⟨10.1016/j.bmcl.2021.128375⟩. ⟨hal-03867355⟩
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