Discovery of thiazolidin-4-one analogue as selective GSK-3β inhibitor through structure based virtual screening. (15th November 2021)

• Record Type: Journal Article
• Authors: Choudhary, Bhanwar Singh; Sukanya, ; Mehta, Pakhuri; Bach, Stephane; Ruchaud, Sandrine; Robert, Thomas; Josselin, Beatrice; Filipek, Slawomir; Malik, Ruchi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 52(2021)
• Publication Date: 2021-11-15
• Subjects: Glycogen synthase kinase 3β -- Structure-based virtual screening -- Protein kinase assay -- Molecular dynamics simulation; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.128375
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Structure based screening and binding energy calculation of Asinex database for GSK-3β inhibition. ADMET analysis of screened hits. In-vitro kinase inhibition and ATP competitive assay. Prediction of binding mode and ligand–protein complex stability by MD simulation. Abstract: 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 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-3β, which were highly comparable to the co-crystallized molecule and hence validating comparative better activity of this compound compared to overall screened molecules.