The design of secretase inhibitors as potential anti Alzheimer agents

Abstract

Alzheimer disease is a severe neurodegenerative disease concerns with a massive impact on health of individuals. Researchers assumed that there are two main neuropathological hypotheses which are; cholinergic hypothesis and beta amyloid plaques hypothesis. The amyloid cascade hypothesis involves the cleavage of amyloid precursor protein (APP) by secretase enzymes and accumulation of β amyloid insoluble peptides in brain because of the incorrect actions of those different secretase enzymes known as α, γ and β secretase. These insoluble plaques trigger a series of events leading to dementia and neuronal dysfunction. Several research and development centers support the idea of discovering a new disease modifying therapy as anti-amyloid agent which inhibits the action of secretase enzymes involved in the pathophysiology. Therefore, we aim to develop a potential new anti-amyloid agent targeting beta secretase enzyme with the least possible side effects to treat AD efficiently and prevent the aggregation of β amyloid plaques. A structure-based pharmacophore approach was used to identify the essential features responsible for the inhibitory activity. A pharmacophore model was generated through using 3 PDB codes, validation and screening against FDA approved drugs database was carried out using LigandScout. It was found that the key features were: two hydrophobic, one positive ionizable, and one hydrogen bond donor interaction. After virtual-screening, 61 hits were found to be fulfilled our generated pharmacophore, 10 hits were selected from them after filtering with their molecular weight and pharmacophore fit score. Then molecular docking for the previously identified 10 hits is performed using MOE software. Best poses for the 10 hits were found to have similar interactions with the amino acids same as in our generated pharmacophore. This could be useful for repurposing of an already existing drug to be effective as BACE-1 inhibitor based on the idea of repurposing of drugs