Probing the intermolecular interactions, binding affinity, charge density distribution and dynamics of silibinin in dual targets AChE and BACE1: QTAIM and molecular dynamics perspective

Abstract

Alzheimer’s disease (AD) is the grievous neurodegenerative disorder. Reportedly, many enzymes are responsible for this disease, in which notably, acetylcholinesterase (AChE) and β-secretase (BACE1) are largely involved for AD. An experimental study reports that silibinin molecule inhibits both AChE and BACE1 enzymes. Present study aims to understand the dual binding mechanism of silibinin in the active site of AChE and BACE1 from the intermolecular interactions, conformational flexibility, charge density distribution, binding energy and the stability of molecule. To obtain the above information, the molecular docking, molecular dynamics (MD) and QTAIM (quantum theory of atoms in molecules) calculations have been performed. The molecular docking reveals that silibinin molecule is forming strong and weak intermolecular interactions with the catalytic site of both enzymes. The QTAIM analysis for the binding pockets of both complexes shows the charge density distribution of intermolecular interactions. The electrostatic potential map displays the electronegative/positive regions at the interaction zone of silibinin with AChE and BACE1 complexes. The MD simulation confirms that the silibinin molecule is stable in the active site of AChE and BACE1 enzymes. The binding free energies of silibinin with both enzymes are more favorable to have the interactions.

Communicated by Ramaswamy H. Sarma

Keywords:

• AChE/BACE1-silibinin
• quantum theory of atoms in molecules
• charge density
• electrostatic potential
• molecular dynamics
• binding free energy

Acknowledgements

The authors thankful to Computer Centre, Periyar University, Salem to use the HPC facility funded by RUSA and C-DAC, Bangalore for providing the GARUDA supercomputing facility.

Disclosure statement

The authors declare that there is no conflict of interest regarding the publication of this paper.

Authors’ contributions

K.S., S.S. and S.S. conceptualized the study and prepared the initial draft; Molecular docking, QM/MM based charge density analysis and MD simulations conducted and results visualized by K.S. P.K. supervised the project, critically appraised the manuscript, and prepared the final draft.

Availability of data and materials

All data and materials of this work are available from the corresponding author on reasonable request.