Virtual screening for new lead compounds for Alzheimer's disease with dual mode of action

Abstract

Alzheimer's disease (AD) is the most common form of dementia which affects people over the age of 65. The exact mechanism of the disease is still unknown what makes development of new drug leads more complicated. First treatment against AD introduced to general use were inhibitors of acetylcholinesterase (AChE). The drugs help patients in daily life but are not able to reverse the progression of the disease and some of them have been withdrawn because of their serious side effects. New and safer drugs with multi-target activity are needed. Galanthamine is a plant alkaloid isolated from Snowdrop (Galanthus sp.) and approved as a drug for the treatment of Alzheimer's disease. It has a dual mode of action – it is an inhibitor of AChE as well as an “allosterically potentiating ligand” at nicotinic acetylcholine receptors (nAChRs). This activity is of great interest in the search for new lead compounds for Alzheimer's and other neurodegenerative diseases. In the search for dual-action enhancers of ACh-mediated neurotransmission natural products including alkaloids isolated from Icelandic club mosses (Lycopodiaceae) were screened using high throughput virtual screening (HTVS) in an X-ray structure of the AChE and in a homology model of the human α7-nAChR. Results of the homology model optimization along with results from the virtual screening will be presented.