γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer's Disease

Background: Alzheimer´s disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than ۳۰ million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid β peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. In this study, we propose an approach by molecular docking to select compounds as γ-secretase inhibitors for decreasing the APP generation. Methods: We selected potential γ-secretase inhibitors by molecular docking in the potential site between Asp۲۵۷, Lue۲۶۸, Asp۳۸۵, Ile۳۸۷, Phe۳۸۸, and Leu۴۳۲ amino acids in presenilin-۱ (PS-۱), using a chemical library of over ۵۰۰,۰۰۰ compounds. Results: Eight compounds (AZ۱ – AZ۸) were selected by molecular docking to develop γ-secretase inhibitors for decreasing the APP generation. Conclusion: AZ۱ – AZ۸ compounds could be interacting in the potential site between Asp۲۵۷, Lue۲۶۸, Asp۳۸۵, Ile۳۸۷, Phe۳۸۸, and Leu۴۳۲ amino acids in PS-۱. These compounds could specifically interact in the binding pocket in PS-۱ to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease.

Keywords:

Amyloid Beta-Protein Precursor , Amyloid Precursor Protein Secretases , Alzheimer’s disease , Molecular Docking Simulation , Presenilin-۱.