Identifying potential Alzheimer's disease therapeutics through GSK-3ß inhibition: A molecular docking and dynamics approach.
Comput Biol Chem
; 111: 108095, 2024 Aug.
Article
in En
| MEDLINE
| ID: mdl-38805865
ABSTRACT
Emerging as a promising drug target for Alzheimer's disease (AD) therapy, glycogen synthase kinase 3ß (GSK-3ß) has garnered attention. This study sought to rigorously scrutinize a compendium of natural compounds retrieved from the ZINC database through pharmacodynamic experiments, employing a 1â¯H-indazole-3-carboxamide (INDZ) scaffold, to identify compounds capable of inhibiting the GSK-3ß protein. Utilizing a multi-step approach, the study involved pharmacophore analysis, followed by molecular docking to select five promising ligands for further investigation. Subsequently, ESMACS simulations were employed to assess the stability of the ligand-protein interactions. Evaluation of the binding modes and free energy of the ligands revealed that five compounds (2a-6a) exhibited crucial interactions with the active site residues. Furthermore, various methodologies, including hydrogen bond and clustering analyses, were utilized to ascertain their inhibitory potential and elucidate the factors contributing to ligand binding in the protein's active site. The findings from MMPBSA/GBSA analysis indicated that these five selected small molecules closely approached the IC50 value of the reference ligand (OH8), yielding energy values of -34.85, -32.58, -31.71, and -30.39â¯kcal/mol, respectively. Additionally, an assessment of the interactions using hydrogen bond and dynamic analyses delineated the effective binding of the ligands with the binding pockets in the protein. Through computational analysis, we obtained valuable insights into the molecular mechanisms of GSK-3ß, aiding in the development of more potent inhibitors.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Molecular Dynamics Simulation
/
Alzheimer Disease
/
Molecular Docking Simulation
/
Glycogen Synthase Kinase 3 beta
Limits:
Humans
Language:
En
Journal:
Comput Biol Chem
Journal subject:
BIOLOGIA
/
INFORMATICA MEDICA
/
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Iran
Country of publication:
United kingdom