INVESTIGATION OF POLYPHARMACOLOGICAL TARGETS OF CHOLINESTERASE INHIBITOR DRUG DONEPEZIL: A STRUCTURE BASED SYSTEMS BIOLOGY APPROACH

Abstract

Drug design and discovery is a process that may involve unintended drug-target interactions resulting in costly drug failures. Drug molecules interacting with multiple targets can lead to various side-effects, a phenomenon called adverse polypharmacology. In the present study, an in silico structure based systems biology approach was undertaken to identify off-targets of Donepezil, a drug that acts as a cholinesterase inhibitor (ChEI) which is prescribed for the treatment of Alzheimer’s disease (AD). Donepezil is reported to cause side-effects that majorly affect gastrointestinal tissues resulting in gastrointestinal haemorrhage, bleeding, peptic ulcers and gastritis. Molecular off-targets of Donepezil were identified using Patch Search, which uses quasi-clique detection method based on local sequence similarity approach. The off-targets present in Homo sapiens having a good RMSD and high coverage value were docked with Donepezil using AutoDock. Two off-targets proteins namely N-alpha-acetyltransferase 60 (NAT) and Heparansulfate ndeacetylase/ n-sulfotransferase were identified that have been previously reported to be involved in causing various gastrointestinal abnormalities and also being associated with H. pylori. H.pylori is a gram negative bacterium that has been reported to be associated with non-gastric diseases such as AD. Therefore, the result of the present study indicates that NAT and Heparan Sulfate n-deacetylase/n-sulfotransferase are probable off-targets of ChEI drug Donepezil prescribed for AD and the interactions of the off-targets with H. pylori may aggravate the aetiology of the side-effects of AD treatment with Donepezil.