Targeting key players in Alzheimer’s disease: bioactive compounds from Moringa oleifera, Desmodium gangeticum, and Centella asiatica as potential therapeutics

Abstract

Alzheimer’s Disease (AD) is one of the critical reasons for dementia around the world, with a huge number of cases being reported every year. The breakdown of Amyloid Precursor Protein (APP) plays a crucial role in AD development. The Beta-site APP Cleaving Enzyme 1 (BACE1) is a highly significant proteolytic enzyme found to be critically involved in the APP breakdown process and generates beta-amyloid plaques in the extracellular neuronal membrane. In this study, we have used natural compounds with cognitive and neuroprotective activities from three plants, Centella asiatica, Moringa oleifera, and Desmodium gangeticum to inhibit the activity of BACE1. We have identified nine compounds out of 73 compounds filtered out from the three plants showing high affinity with the catalytic dyad region of BACE1 through molecular docking studies. Interestingly, the 200 ns molecular dynamics simulation study further confirmed the stability of the complexes formed between 9 compounds and the BACE1 protein. Furthermore, the free energy calculations also revealed these complexes possess favorable energies. Astilbin, Delphinidin 3-glucoside, and kaempferol 7-O-glucoside showed good binding affinity and structural stability when compared to other compounds and the control CNP520. Following a preliminary screening, the Astilbin compound was chosen based on the grounds of binding affinity, ADMET Properties, Hbond formation, Molecular Dynamic simulation, and MM-PBSA studies. A subsequent 1microsecond molecular dynamics simulation was conducted for the Astilbin complex. Through microsecond simulation, it was found that Astilbin alters BACE1's behavior and induces conformational rearrangements. Thus, this study opens a gateway to inhibit the activity of BACE1 protein through Astilbin thereby disclosing the possibility of managing Alzheimer’s Disease.

Communicated by Ramaswamy H. Sarma

Keywords:

• Alzheimer’s disease
• BACE1
• natural compounds
• molecular docking
• molecular dynamics simulations

Acknowledgments

The authors are grateful to the management of Vellore Institute of Technology (VIT) for providing all the facilities to carry out this research article. Also, the authors are grateful to the Centre for Technical Support (CTS) VIT for providing NVIDIA- GPU access.

Author contributions

The corresponding author Sajitha Lulu S conceived the idea, and the first author Premkumar T designed the work did the data collection, and performed the analysis. The first draft of the manuscript was written by Premkumar T and corresponding author Sajitha Lulu S revised and approved the final manuscript.

Disclosure statement

No potential competing interest was reported by the authors.

Additional information

Funding

This research article is not funded by any organization.