Uncovering an Improved Version of Donepezil, an Alzheimer’s Treatment

Alzheimer’s disease, a form of dementia that declines cognitive function, is one of the world’s most prevalent diseases, currently with no cure discovered. Many drug therapies for the treatment of Alzheimer’s are centered around the cholinergic hypothesis, which states that the decrease of acetylcholine (ACh), a crucial neurotransmitter, is the start of the development of Alzheimer’s. To counter this, most Alzheimer’s drugs, including the very popular Donepezil (approved in 1996), are acetylcholinesterase inhibitors. These medications consist of small molecules that prevent ACh being broken down by the acetylcholinesterase enzyme, preserving ACh in the brain. To discover more efficient acetylcholinesterase inhibitors using modern methods of drug discovery, a computer model of Donepezil binded to an acetylcholinesterase protein was taken as a source of inspiration and put into SeeSAR to computationally create small molecules that could bind better to the enzyme. The resulting small molecules and their properties as a drug were analyzed utilizing SwissADME to determine which could be used in a medical treatment setting