Virtual screening for new lead compounds for Alzheimer's disease with dual mode of action
Galanthamine is a plant alkaloid isolated from Snowdrop (Galanthus sp.) and approved as a drug for the treatment of Alzheimer's disease. Galanthamine has a dual mode of action – it is an inhibitor of acetylcholinesterase (AChE) as well as an “allosterically potentiating ligand” at nicotinic acetylcholine receptors (nAChRs). Similar dual-action profiles are known for physiostigmine, codeine and the neurotransmitter serotonin and are 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 at the α7-nAChR. Results of the homology modeling at the α7-nAChR along with results from virtual screening will be presented.