Screening of Polyphenolic compounds to identify dual inhibitors against Glycogen Synthase 3β and Acetylcholinesterase for the treatment of Alzheimer’s Diseases

Abstract

Alzheimer’s diseases is a neurodegenerative progressive diseases accompanied by complex pathology. Because of its complex pathology, multi-target ligands are considered as an attractive strategy for new drug development against AD. In this context dual inhibition of AChE and GSK-3β can be considered as an important strategy. In this work, various polyphenolic compounds from the literature were collected and evaluated against AChE and GSK-3β using molecular docking. The results indicated good binding potential of all the docked compounds for GSK-3β (9kcal/mol), while weak to good binding potential for AChE (8 to 12kcal/mol). The binding mode analysis of GSK-3 docked complexes showed interactions with key residues like Asp133 and Val135 which are important for molecular recognition. Additionally, the docked compounds showed interactions with Leu132, Arg141 and Cys199, the residues important for potency and selectivity. With respect to AChE, the compounds mostly occupied peripheral aromatic site in the active site of AChE, the site important for binding of ligands and inhibitor. The binding mode analysis showed interactions with key residues Tyr124, Ser293 and Arg296 important for substrate binding and recognition. Further the polar interactions were also noted for His447 and Ser203 (residues important for Ach hydrolysis) in some of the identified ligands. Overall the work resulted in the identification of eight compounds 5'-geranyl-5,7,2',4'tetrahydroxyflavone-2, Kuwanon E 4, Gossypetin, Kaempferide, Galangin, Kaempferol, baicalein and Ellagic acid with the potential dual inhibition of AChE and GSK-3β. It should be noted that kaempferide was not reported in the literature for AChE inhibition, while except baicalein none of the compounds were reported for GSK-3β. Further, the eight identified compounds were subjected for ADME profiling using SwissADME which showed their drug like character. Therefore, based on the results from this study, the above mentioned eight compounds can be looked upon with the potential of dual inhibition against AChE and GSK-3β.