Acetylcholinesterase inhibition of Alzheimer’s disease: identification of potential phytochemicals and designing more effective derivatives to manage disease condition

Abstract

Alzheimer’s disease (AD) is a brain disease characterized by gradual memory loss and cognitive impairments. Acetylcholinesterase (AChE) inhibitors—such as donepezil, memantine, and tacrine—are FDA-approved medications for AD treatment. Due to the lack of their efficacy and higher side effects, many researchers have been searching for effective and safer alternatives. In this study, experimentally proved phytochemicals against brain diseases were screened based on their binding energies to the target site of AChE, pharmacokinetic properties, and drug-likeness. Although some phytochemicals showed higher binding affinities than the control drug (donepezil), they did not show permeability across the blood-brain barrier (BBB). However, berberine, anthocyanin, and diterpene alkaloid can cross the BBB and showed good binding affinities of −10.3, −10.1, and −10.2 kcal/mol, respectively. MD simulation and PCA of the simulation data of the protein and protein-ligand complexes proved that the complexes are stable in the biological environment. A total of 16 derivatives of berberine and 3 derivatives of anthocyanin also showed higher binding energies compared to the binding affinity (−11.5 kcal/mol) of the donepezil. The derivatives were designed by substituting –F, –CF3, –CN, and –NH2, and provided higher docking scores due to increasing of nonbonding interactions. MM/GBSA calculations show that the binding free energies of the best predicted derivatives of diterpene alkaloid, anthocyanin, and berberine (DA22, AC11, and BB40) are −100.4 ± 8.4, −79.3 ± 8.7, and −78.3 ± 10.7 kcal/mol, respectively, with the protein. Overall, this study was successful in finding new, highly effective, and possibly safer inhibitors of AChE.

Communicated by Ramaswamy H. Sarma

Schematic representation of the drug design process for this study.

Keywords:

• Alzheimer’s disease
• lead molecules
• phytochemicals
• molecular docking-ADMET
• MD simulations
• PCA
• MM/GBSA
• derivative design

Acknowledgements

All the authors are grateful to Dr. Mohammad A. Halim, Assistant Professor of Chemistry and Biochemistry, Kennesaw State University for his support running molecular dynamics simulations using YASARA platform for a few initial simulations as our YASARA platform was engaged with other projects that time.

Author contributions

H.K.K did initial study, computations, pharmacokinetic, structural analysis, manuscript writing, and revision; K.S designed the derivatives, synthetic route, mm-gbsa, and write-up for that part; M.S.R guided the research work and conducted a part of MD simulation, PCA analysis, and outlined manuscript writing, and final review.

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.