Molecular Docking and Dynamics Simulation of Natural Phenolic Compounds with GSK-3β: A Putative Target to Combat...

In this study, molecular docking analysis was performed to evaluate the binding affinity of 52 plant-based phenolics with the GSK-3β active sites. Moreover, Molecular Dynamics (MD) simulation was conducted to investigate the stability of interactions between the topranked phenolics and residues within the GSK-3β active sites.

Molecular docking and MD simulations were performed using AutoDock and Discovery Studio Client software, respectively. Thereafter, pharmacokinetic and toxicological properties of top inhibitors were predicted using bioinformatics web tools. This study aimed to identify the most effective amino acids involved in the inhibition of GSK-3β based on the most stabilizing interactions between the residues and compounds, and also by considering the degree centrality in the ligand- amino acid interaction network for GSK-3β.

It was observed that procyanidin and amentoflavone could bind to the GSK-3β active sites at the picomolar (pM) scale as well as the binding affinity of ΔG _binding < -13 kcal/mol, while the inhibition constant for theaflavin 3'-gallate, procyanidin B4, and rutin was calculated at the nanomolar (nM) scale, suggesting that these phenolic compounds can be considered as potential effective GSK-3β inhibitors. Furthermore, Val70, Ala83, Val135, and Tyr134 were found to be the most important amino acids involved in the inhibition of GSK-3β.

The results of the current study may be useful in the prevention of several human disorders, including COVID-19, cancers, Alzheimer's disease, diabetes mellitus, and cardiovascular diseases. However, wet-lab experiments need to be performed in the future.