Discovery of small molecules from natural compound databases as potent retinoid X alpha receptor agonists to treat Alzheimer's disease

Alzheimer's is characterized as a progressive neurodegenerative disease due to beta-amyloid accumulation in the brain. Some previous studies reported that RXR agonists could be effective in the treatment of Alzheimer's disease. There are currently numerous attempts being made to discover a natural RXR agonist that is more potent than 9-cis-retinoic acid (9CR). One of the most efficient resources for finding high-potential compounds is natural databases. In this study, 81215 compounds from the IB screen library as natural databases were docked against the RXR-alpha binding site. The best compounds discovered interact with the RXR-alpha binding site with a lower binding energy (-11 to -13 kcal/mol) than the binding energy of -10.94 kcal/mol for 9-cis, which means that these compounds could interact stronger with RXR-alpha than 9CR. All selected compounds could pass the blood-brain barrier. Physiochemical properties assessment indicated that all compounds passed Lipinski's rule and had the potential to be oral drug candidates. The stability of protein-ligand complexes during a timescale of 100 ns by Molecular Dynamics simulation demonstrated that all compounds could effectively interact with the RXR binding site. The molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) represented that all selected hit compounds had a better binding affinity to the alpha RXR binding site compared to 9CR, which means these hit compounds had potential drug candidates for the treatment of Alzheimer's disease. However, experimental assessment is needed to validate this result.Communicated by Ramaswamy H. Sarma