Discovery of potent and selective butyrylcholinesterase inhibitors through the use of pharmacophore-based screening

Cholinesterase inhibitors have long been used in the treatment of Alzheimer’s Disease (AD) via the protection of acetylcholine levels. However, recent research has shown that the specific inhibition of butyrylcholinesterase (BChE) could better ameliorate symptoms within patients. In addition, it has recently been shown that selective inhibition of BChE can also significantly attenuate the toxicity and physiological effects of heroin. Currently, there are no specific and potent inhibitors of BChE approved for use in AD or heroin abuse. Through a combined use of in silico and in vitro screening, we have found three compounds with sub-50 nM IC₅₀ values that specifically target BChE. These newly discovered BChE inhibitors can act as the lead scaffolds for future development of the desirably potent and selective BChE inhibitors.