Applying virtual screening approach to find out effective agonist against RXR (retinoid X receptor) as promising candidates to treat Alzheimer disease

Introduction: Alzheimer's is neurodegenerative disease that causes accumulation of extensive amyloid-betain the brain. The prevalence Alzheimer of patients increased exponentially so that in United states estimates۱۳.۷ million people will be affected by Alzheimer by ۲۰۸۰. Alzheimer's patients can be classified into twodifferent types including Sporadic or late-onset AD (LOAD) with prevalence of ۹۵% and early-onset AD(EOAD). In the LOAD, one of the predominate risk factor gene is APOE which dysregulation of this geneincrease accumulation of amyloid-beta. So regulation the expression of APOE by RXR receptor astranscriptional regulator of APOE by designing Agonist against RXR receptor could be control clearance ofamyloid-beta and decrease symptoms of Alzheimer.Material and Methods: Two herbal Database (TCM and IBscreen) were selected as ligand libraries. Pharmitwebserver was chosen to check properties of small molecules based on Lipinski's rules. The selected smallmolecules which pass Lipinski's rules were applied to dock by SMINA package against binding site of RXRreceptor. The small molecules that effectively interact with RXR binding site nominated for cytotoxic andblood barrier properties analysis by OSIRIS Data Warrior and BBB predictor. Small molecules that couldpass blood-brain barrier and have not mutagenesis, tumorigenic, reproductive effect properties were enteredin Molecular Dynamic simulation and efficacy of their interaction were checked by MM/PBSA package.Results and Discussion: Among total compounds of TCM and IBscreen, around thirty compounds passLipinski's rules and effectively interact with binding site of RXR receptor. Cytotoxic and blood brain barrieranalysis revealed that all these compounds have no mutagenesis, tumorigenic, reproductive effect and ableto pass blood brain barrier. Molecular dynamic simulation discovered that five compounds able to interactefficiently during simulation. MM/PBSA analysis figured out that these compounds effectively bind tobinding site of RXR receptor.

کلیدواژه ها:

Alzheimer disease ، virtual screening ، retinoid X receptor ، Molecular Dynamics simulation ، Molecular docking