Development of New Chemical Molecules to Inhibit GSK 3and#946; Enzyme to have Neuroprotective activity

Abstract

Combination approach of both LBDD and SBDD, five hits comprising isoquinoline, purine, thiazolidinedione, benzothiophene and quinazolinone scaffolds were identified. Enzyme inhibition assay was performed to confirm inhibitory potency of lead molecules. Identified hits when evaluated for enzyme inhibition efficacy, showed inhibitory concentration (IC50) from 825 nM to 1.116 µM and were 23-57-fold selective to GSK-3and#946; over CDKS. Interaction of lead molecules with K60, V61, R141 and D200 may enhance selectivity of molecules to GSK-3and#946;. Interaction with D133, Y134 and V135 was assumed providing potency of leads towards GSK-3and#946;. Amongst all lead molecules, a purine derivative (Molecule G3) exhibited high potency possessing lowest IC50 value (0.825 µM). Energy minimized lead molecule conformers, upon docking revealed 2-cationic, ionic, and small atom hydrophobic interactions. These interactions were supported by H-bond interaction of water with key amino acid residues of GSK-3and#946;. TRIM11 was found involved in differentiation of neuroblastoma SH-SY5Y cells by RA. The proposed mechanism that underlies during OGD and upon inhibition of GSK-3and#946; activity. OGD experiment activates GSK-3and#946; resulting inactivating AKT1 by and#946;-arrestin2/PP2A complex. Activation of GSK-3and#946; destabilize and#946;-catenin by phosphorylates and subsequent degradation by TRIM11. Degradation might be dependent to GSK-3and#946; mediated phosphorylation. Restriction of and#946;-catenin translocation due to its degradation affects transcription of survivin, GAP43, Ngnl, NeuroD2, and TRIM11 that mediates apoptosis, compromised in neuronal functioning and proteolytic degradation. Simultaneously, GSK-3and#946; activation disrupts the mitochondrial functioning and activation of caspase-3 leading to necrosis and neuronal apoptosis. Treatment with standard GSK-3and#946; inhibitor AR-A014418 and lead inhibitor molecule G3 stabilizes AKT1/GSK-and#946; / and#946;-catenin pathway, maintains GSK-3and#946; in inactive state, prevents dephosphorylation thereby reduces and#946;-catenin degradation and mediates its translocation.