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

Bhanwar Singh Choudhary; Sukanya; Pakhuri Mehta; Stephane Bach; Sandrine Ruchaud; Thomas Robert; Beatrice Josselin; Slawomir Filipek; Ruchi Malik

doi:10.1016/j.bmcl.2021.128375

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

Bioorg Med Chem Lett. 2021 Nov 15:52:128375. doi: 10.1016/j.bmcl.2021.128375. Epub 2021 Sep 21.

Authors

Bhanwar Singh Choudhary¹, Sukanya¹, Pakhuri Mehta², Stephane Bach³, Sandrine Ruchaud⁴, Thomas Robert³, Beatrice Josselin³, Slawomir Filipek², Ruchi Malik⁵

Affiliations

¹ Department of Pharmacy, Central University of Rajasthan, Bandarsindari, Ajmer, Rajasthan 305817, India.
² Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, ul. Pasteura 1, 02-093 Warsaw, Poland.
³ Sorbonne Université, CNRS, FR2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, 29680 Roscoff, France; Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France.
⁴ Sorbonne Université, CNRS, UMR8227, Integrative Biology of Marine Models Laboratory (LBI2M), Station Biologique de Roscoff, 29680 Roscoff, France.
⁵ Department of Pharmacy, Central University of Rajasthan, Bandarsindari, Ajmer, Rajasthan 305817, India. Electronic address: [email protected].

PMID: 34560262
DOI: 10.1016/j.bmcl.2021.128375

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.

Keywords: Glycogen synthase kinase 3β; Molecular dynamics simulation; Protein kinase assay; Structure-based virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors*
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Molecular Structure
Neuroprotective Agents / chemical synthesis
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship
Thiazolidines / chemical synthesis
Thiazolidines / chemistry
Thiazolidines / pharmacology*

Substances

Neuroprotective Agents
Protein Kinase Inhibitors
Thiazolidines
Glycogen Synthase Kinase 3 beta