Study of structural and dynamic changes of GSK3β protein in the presence of CHIR99021 ligand using molecular simulation and docking

Glycogen synthase kinase 3 beta (GSK3β) is a multifunctional serine/thronine kinase that play as a bottleneck protein in the WNT signaling pathway in various functions of pluripotent stem cells (PSCs) such as Self-renewal, survival and differentiation. Since the inhibition of GSK3β leads to the differentiation of PSCs, the use of appropriate inhibitors that inhibit GSK3β at lower concentrations can be economically affordable. One of the most important inhibitors is CHIR99021, which can improve the culture and differentiation systems of PSCs. Present study aimed to investigate the molecular dynamics (MD) simulation such as Root Means Square Deviation (RMSD), Root Means Square fluctuation (RMSF), number of hydrogen bonds, principal component analysis (PCA), radius of gyration, Gibbs free energy landscape, in the presence and absence of CHIR99021 were evaluated and the stability and structural changes of GSK3β protein were simulated using GROMACS 2021.1 software. In addition, the pharmacokinetic properties of this compound were predicted using Schrӧdinger, LLC, New York, NY, Release 2015-2 software. The results of these studies showed that CHIR99021 binds to the active site of GSK3β through hydrogen bonding and produces its inhibitory effect, thus causing instability of the GSK3β structure. Docking and computational analysis confirmed that this chemical compound can be effectively used for directing cell fate and differentiation of PSCs.