Nicotinic acetylcholine receptor (nAChR) is a pentameric protein assembly that belong to the Cys-loop Ligand Gated Ion Channels superfamily. Several neuronal subtypes of nAChR pose a promising target for treatment of such disorders as nicotine addiction, depression, schizophrenia, cognition deficits and treatment of pain. Most of commonly used drug molecules and their metabolites interact with the inner surface of the ion channel by a mechanism of non-competitive inhibition associated with disturbing the flux of ions through the channel. Binding of allosteric ligand molecules to outer and inner surface of the extracellular domain (ECD) of nAChR play important roles in coupling agonist binding to the channel gating. In our project we made two sets of molecular modeling simulations for two distinct part of nAChR and its interactions with ligand molecules. Models of 1) the ion channel domain and 2) the extracellular domain were developed for several subtypes of the receptor and were used in docking simulations of ligands interacting at these locations.

In the project 1) the molecular model of transmembrane domain of the nAChR obtained using cryoelectron microscopy of Torpedo marmorata (PDB id: 2BG9) was used. We further modified this model to represent models of the several human neuronal and muscular subtypes. Docking procedures of a flexible ligand into the rigid model of the ion channel were performed and allowed classification of ligands in respect to their binding energies. Obtained result for the interactions with ion channel indicated that ligands stably interact with the surface of the channel formed by an assembly of five transmembrane helices M2. The binding energy estimated in simulations can be related to experimental values.

In the project 2) the molecular models of extracellular domain of nAChR obtained from Lymnaea stagnalis (PDB id: 1UV6) and Gloeobacter violaceus (PDB id: 3EAM) were used. We constructed the models representing different neuronal subtypes of ECD of nAChR using homology modeling. Obtained models were used for docking simulations of such ligands as galanthamine, physostygmine, codeine, 5-hydroxytryptamine, ketamine and its metabolites. Obtained results suggest that allosteric potential ligands bind to different locations than acetylcholine and affect the function of the receptor.

Studied compounds show different modes of allosteric modulation but all of them play important role in regulation of cholinergic transmission in the brain. Various groups of ligands interact in different modes with distinct regions of the nicotinic acetylcholine receptor.

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