In-silico Studies of Ursodeoxycholic Acid From Red Sea Weed Jania Rubens By_aina_et Al

Alzheimer's disease, one of the neurodegenerative disorders, is marked by the gradual weakening of nerve cells in the brain or peripheral nervous system, along with abnormal protein aggregation. While there have been significant initiatives towards management of the condition, however there is still a dearth of data on candidate phytochemicals and analogues in the treatment of this condition. Herein we present alkaloids derived from the marine algae Jania rubens as inhibitors of human acetylcholinesterase in addressing Alzheimer's disease. Using in-silico tools like Protox II and SwissADME, forty isolates were screened for toxicity and ADME properties, while molecular docking simulations was performed using PyRx 0.8 AutoDock Vina Wizard and Discovery Studio 2020. A 50 nanoseconds molecular dynamic (MD) simulation was performed on GROMACS via LINUX environment, and CHARMM 36 force field. Ursodeoxycholic acid (AL20), an isolate from J. rubens , exhibited strong inhibitory activity against 4ey6 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 AL20 to be 73% hepatotoxic. Thereafter, seven derivatives (AL20A-G) were designed to improve properties for drug likeness. The amide analogue, 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 AChE, forming three hydrogen bonds with amino acid residues Pro290, Ser293, and Leu289. The BOILED-Egg model predicted favorable gastrointestinal absorption and blood-brain barrier penetration for AL20E, indicating its potential as a CNS-active drug. Density Functional Theory (DFT) and Molecular dynamics analyses confirmed the chemical stability of AL20E, making it a promising candidate for anti-Alzheimer drug development. 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, acetylcholinesterase inhibitor with enhanced drug-likeness. This study thereby presents AL20E for consideration as a lead compound in the development of novel Alzheimer’s therapeutics.