Cigarette smoking is considered, nowadays, to be a significant public health problem. Recent estimates indicate that approximately 1/4 th of the world’s population smokes 1 and that smoking is the second most prevalent cause of death in the world 2 . Currently, the FDA- approved smoking cessation drugs, such as varenicline, are only moderately effective in reducing the symptoms of nicotine withdrawal and may cause undesirable side effects. Consequently, there is a growing need to develop new smoking cessation agents with improved effectiveness and tolerability.
Nicotine is the principal biologically psychoactive agent in tobacco, and it binds to the nicotinic acetylcholine receptors (nAChRs) 3 . These receptors mediate synaptic transmission in the nervous system and are therapeutic targets for various neurodegenerative diseases, psychiatric and neurodevelopmental disorders, including nicotine addiction 3 . Over the last decades, nAChRs have been widely explored, and our understanding of their molecular mechanisms has made extensive progress. However, despite a plethora of available structural and biochemical data, it is still not clear how ligand binding induces the
conformational changes necessary to modulate the receptor’s dynamics. Answering this question requires knowledge of the dynamics of the protein and the identification of the conformational changes that take place upon ligand binding. Molecular dynamics (MD) simulations offer a highly effective method to identify, ‘assay’ and analyse functionally important motions of proteins and recently we have used a combination of equilibrium and nonequilibrium molecular dynamics simulations to map dynamic and structural changes
induced by nicotine in two of the most relevant nAChRs, namely the α4β2 4,5 and the α7 4,6 subtypes. Our simulations reveal a striking pattern of communication between the agonist-binding pockets and the transmembrane domains and show the sequence of conformationalchanges associated with the initial steps of signal propagation.
1. “World Cancer Report 2014”, WHO, 2014
2. “The Health consequences of smoking: nicotine addiction”, CDC, 1988
3. Dineley et al. Trends Pharmacol Sci, 36, 96-108, 2015
4. Campello et al. Chem, 4, 1710-1725, 2018
5. Oliveira et al. Structure, 27, 1171-1183, 2019
6. Oliveira et al. J Am Chem Soc, 141, 19953-19958, 2019
Building: Yersin (OMCS)
Room: 2nd floor, meeting room
Address: 25-28 Rue du Dr Roux, 75015 Paris, France