Identification of novel small molecules against GSK3β for Alzheimer's disease using chemoinformatics approach

Abstract Alzheimer's disease is a rapidly increasing neurodegenerative disease. It is a multifactorial disease and also a global threat. Several enzymes are implicated in the disease in which Glycogen Synthase Kinase 3 beta is a key enzyme to increase the disease progression by the hyperphosphorylation of the tau protein. We have used an integrative chemoinformatics and pharmacokinetics approach for the identification of novel small molecules. We have retrieved a subset from the ZINC database (n = 5,36,709) and screened against GSK3β in four steps. From here top 298 potent compounds were selected and employed for their pharmacokinetics analysis. We had seen that 29 compounds showed the key characteristics to be a novel drug candidate therefore, all these compounds were employed for redocking studies using Autodock Vina and Autodock. This analysis revealed that four compounds were showing good binding affinity. All these four compounds were employed for MDS analysis of 100 ns From here using a bunch of MD analyses we have found that out of four compounds GSK3β-ZINC21011059 and GSK3β-ZINC21011066 act as a stable protein-ligand complex. Therefore we proposed ZINC21011059 and ZINC21011066 can serve as a novel compounds against GSK3β and predicted scaffold can be used for further optimization towards the improvement of isoform selectivity, and warranting further investigations towards their in vitro and in vivo validation of the bioactivity .