<i>In Silico</i> Insights into Marine Natural Products as AChE and BChE Inhibitors

Background: Alzheimer’s Disease (AD), a progressive neurodegenerative disorder, remains a significant global health challenge. Aim: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors are crucial in managing the symptoms of AD, and exploring new, potent inhibitors is an ongoing area of research. Methods: This study investigates the therapeutic potential of marine-derived natural products as AChE and BChE inhibitors through a detailed in silico approach. A total of 675 compounds from the COCONUT Natural Product Database were screened, with compounds CNP0200466, CNP0325153, and CNP0017810 identified as top candidates for AChE inhibition, and compounds CNP0310051.1 and CNP0313638 identified for BChE inhibition. Result: The docking analysis revealed that these compounds exhibited significantly higher binding affinities compared to the standard drugs, Galantamine and Rivastigmine. For AChE (PDB: 4EY7), Galantamine showed a binding score of -9.6 kcal/mol, while compounds CNP0200466, CNP0325153, and CNP0017810 demonstrated stronger affinities of -12.6, -11.5, and -10.8 kcal/mol, respectively. Similarly, for BChE (PDB: 5DYW), Rivastigmine showed a binding score of -7.2 kcal/mol, while compounds CNP0310051.1 and CNP0313638 exhibited superior affinities of -11.0 and -10.9 kcal/mol, respectively. Pharmacokinetic evaluation using SwissADME confirmed that all compounds exhibited high gastrointestinal absorption, blood-brain barrier permeability, and no P-glycoprotein interaction, suggesting their potential for efficient CNS targeting. ADMET analysis revealed favorable renal clearance, non-hepatotoxic profiles, and no significant AMES toxicity. These results indicate that the marine-derived compounds identified in this study possess both high efficacy and favorable safety profiles. Conclusion: In conclusion, the promising docking results, coupled with favorable pharmacokinetic and toxicological properties, make these marine-derived compounds strong candidates for further preclinical and clinical studies. Major Findings: The findings highlight the potential for these compounds to serve as novel therapeutic agents for Alzheimer’s disease, paving the way for more effective treatments for this devastating disorder.