In silico evaluation of ursodeoxycholic acid from Jania rubens and its analogs as potential anti-Alzheimer’s agents

Alzheimer’s disease (AD), one of the neurodegenerative disorders, is marked by the gradual degeneration of nerve cells in the brain or peripheral nervous system, along with abnormal protein aggregation. While significant efforts have been made to manage AD, a dearth of data remains on candidate phytochemicals and analogs in its treatment. Herein, we present alkaloids derived from the marine algae Jania rubens as potential inhibitors of human acetylcholinesterase (AChE) relevant to AD therapy. Using in silico tools, such as Protox II and SwissADME, 40 isolates were screened for toxicity and absorption, distribution, metabolism, and excretion properties. Molecular docking simulations were performed using PyRx 0.8, AutoDock Vina Wizard, and Discovery Studio 2020. A 50-nanosecond molecular dynamics simulation was performed using the Groningen Molecular Simulation in the LINUX environment and bio-organic molecules force field simulation (CHARMM 36). Ursodeoxycholic acid (AL20), an isolate from J. rubens, exhibited strong inhibitory activity against AChE with a binding energy of −8.5 kcal/mol, surpassing standard anti-Alzheimer drugs donepezil (−8.3 kcal/mol), galantamine (−7.7 kcal/mol), and rivastigmine (−6.4 kcal/mol). However, in silico data revealed a 73% probability of hepatotoxicity for AL20. Thereafter, seven derivatives (AL20A–G) were designed to improve properties for drug likeness. The amide analog, AL20E, showed superior inhibitory activity (−9.0 kcal/mol) and non-toxicity compared to AL20 and the standard drugs. This derivative also demonstrated strong interactions with the AChE enzyme, forming three hydrogen bonds with amino acid residues Pro290, Ser293, and Leu289. The brain or intestinal estimated permeation model predicted favorable gastrointestinal absorption and blood–brain barrier penetration for AL20E, indicating its potential as a central nervous system-active drug. Density functional theory and molecular dynamics analyses confirmed the chemical stability of AL20E, making it a promising candidate for the development of an anti-Alzheimer drug. This study highlights AL20E ([4R]-4-[{3S,7S,8R,9S,10S,13R,14S,17R}-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H cyclopenta{a}phenanthren-17-yl]pentanamide) as a non-toxic, AchE inhibitor with enhanced drug-likeness. This study thereby presents AL20E for consideration as a lead compound in the development of novel Alzheimer’s therapeutics.