Use of ligand-based pharmacophore modeling and docking approach to find novel acetylcholinesterase inhibitors for treating Alzheimer's

Abstract

Alzheimer's disease is a neurological disorder in which the patient suffers from memory loss and impaired cognitive abilities. Though the main cause of the disease is not yet known, depletion of neurotransmitter at synaptic junctions, accumulation of insoluble beta amyloid plaques and neurofibrillary tangles are the main pathologies associated with it. The FDA approved drugs for alzheimer's belong to the category of acetylcholinesterase inhibitors. But most of the drugs have been observed to be associated with adverse side effects. In this study, we have developed a pharmacophore (responsible for interaction with acetylcholinesterase active site) based on the already existing drugs and drug candidates. This pharmacophore was used to search for novel AChE inhibitors with altogether different chemical scaffold using high throughput virtual screening and docking studies. Finally, we have reported two compounds, OPA and OMT, which possess high affinity for catalytic site of AChE enzyme and thus, can be considered as potential AChE inhibitors for the symptomatic treatment of Alzheimer's.

Keywords: Acetylcholinesterase inhibitors; Alzheimer's; Drug design; Molecular docking; Pharmacophore.