Binding and stability of indirubin-3-monoxime in the GSK3β enzyme: a molecular dynamics simulation and binding free energy study

Abstract

Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder which alters the memory of a person. It is a common form of senile dementia characterized by memory loss, personal skills and disorientation. The current treatment for AD is fully focused to control the disease based on symptoms. Based on the tau hypothesis, GSK3β is an interesting drug target, this also alters the course of AD. The recent experimental report outlines that the indirubin derivatives inhibit GSK3β, however, the detailed binding mechanism of indrubin-GSK3β is not yet known. To understand the exact binding mechanism of indirubin derivatives in the active site of GSK3β, the molecular conformation, intermolecular interactions, charge density distribution, electrostatic properties and the stability were determined. To accomplish this, indirubin derivatives were screened via molecular docking and further molecular dynamics (MD) and QM/MM-based charge density analysis have been performed. The molecular docking was carried out to investigate the binding affinity and the intermolecular interactions of indirubin molecule in the active site of GSK3β. QM/MM based charge density (CD) analysis has been carried out to emphasize the nature of chemical bonding (topology of electron density) and the electrostatic properties of ligand in the binding pocket. We have performed the CD analysis of intermolecular interaction between indirubin-3-monoxime and the active site amino acids of GSK3β. Further, the stability of the molecule has been confirmed from the MD simulation and the binding free energy of the indirubin-3-monoxime-GSK3β complex has been determined using MM/PBSA method to validate the binding affinity of indirubin-3-monoxime.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• GSK3β
• indirubin
• QM/MM-based charge density analysis
• MD simulation and MM/PBSA calculation

Acknowledgments

K.S. thanks Periyar University for University Research Fellowship (URF) to carry out this research work. The authors thank Schrödinger, Bangalore, India, to use the software for this study and C-DAC, Bangalore for providing the GARUDA supercomputing facility.

Disclosure statement

No potential conflict of interest was reported by the authors.