Virtual Screening, Toxicity Evaluation and Pharmacokinetics of Erythrina Alkaloids as Acetylcholinesterase Inhibitor Candidates from Natural Products

Afri Permana, Abd Wahid Rizaldi Akili, Ari Hardianto, Jalifah Binti Latip, Allyn Pramudya Sulaeman, Tati Herlina
https://doi.org/10.2147/AABC.S495947

Abstract

Purpose

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with limited treatment options, necessitating thedevelopment of safer and more effective therapies. The potential of alkaloids derived from the genus Erythrina as acetylcholinesterase(AChE) inhibitors is being investigated to enhance acetylcholine levels in the brain, which is crucial for the treatment of AD. Theobjective of this study is to identify Erythrina alkaloids with strong inhibitory capacity against AChE and favorable pharmacokineticprofiles.

Materials and Methods

A multi-step computational approach was employed, beginning with the virtual screening of 143 Erythrinaalkaloid structures using molecular docking against the human AChE crystal structure. The binding affinities were compared with theknown AChE inhibitor, galantamine. The top alkaloid, 8-oxoerymelanthine (128), was subjected to further analysis through moleculardynamics simulations, with the objective of evaluating its stability and interactions. In silico ADMET predictions were conducted toassess the pharmacokinetic properties. The applicability of Lipinski’s Rule of Five was applied to evaluate oral drug-likeness.

Results

8-Oxoerymelanthine (128) exhibited the highest binding affinity and remarkable stability in molecular dynamics simulations.The toxicity predictions indicated a low risk of mutagenicity, hepatotoxicity, and cardiotoxicity. Pharmacokinetic assessmentsindicated good absorption, moderate blood-brain barrier penetration, and favorable metabolic and excretion profiles, supporting itspotential as an orally active drug candidate.

Conclusions

8-Oxoerythmelanthine (128) exhibits strong potential as an AChE inhibitor with a favorable balance of efficacy, safety,and pharmacokinetic properties. These results warrant further investigation in preclinical and clinical studies to validate its therapeuticpotential and safety for Alzheimer’s disease treatment.

Keywords:

Erythrina alkaloid; Pharmacokinetics; In silico; Acetylcholinesterase inhibitors; Virtual screening