A DRUG REPURPOSING APPROACH THROUGH PHARMACOPHORE MODELING AND MOLECULAR DOCKING TO MANAGE ALZHEIMER’S DISEASE VIA GSK-3β MODULATION

Abstract

Alzheimer’s Disease is progressive disorder whose pathophysiology and therapeutic status still stands unclear. As of now, all the therapies are confined to symptomatic relief, disease modifying therapies are therefore the need of the hour. Modulation in Wnt cascade has already been linked to varied disorders which include AD and type 2 diabetes mellitus too. The interlink between insulin signaling pathway and Wnt cascade has been well acknowledged through a number of preclinical and clinical studies. This in silico-based study is focused upon investigating the link between curative effects of FDA approved anti- diabetic drug and Wnt signaling cascade. We prepared a library consisting of 143 FDA approved antidiabetic medicines with an aim of repurposing them as GSK 3 beta inhibitor, which is present in increased amounts in AD brain. Pharmacophore modelling was performed for these drugs and the lead hits were then subjected to ligand- protein based molecular docking followed by molecular dynamics simulation. ZINC04803471 emerged as a clear winner that can inhibit GSK 3 beta, which leads to beta catenin degeneration and thereby downregulates the canonical Wnt signaling cascade in the AD brain. Although this is just a tip of an iceberg, further in vitro investigation is necessary to validate the effectiveness of the compound.