Blocking of the nicotinic acetylcholine receptor ion channel by chlorpromazine, a noncompetitive inhibitor: A molecular dynamics simulation study.

A large series of pharmacological agents, distinct from the typical competitive antagonists, block in a noncompetitive manner the permeability response of the nicotinic acetylcholine receptor (nAChR) to the neurotransmitter acetylcholine. Taking the neuroleptic chlorpromazine (CPZ) as an example of such agents, the blocking mechanism of noncompetitive inhibitors to the ion channel pore of the nAChR has been explored at the atomic level using both conventional and steered molecular dynamics (MD) simulations. Repeated steered MD simulations have permitted calculation of the free energy (approximately 36 kJ/mol) of CPZ binding and identification of the optimal site in the region of the serine and leucine rings, at approximately 4 A from the pore entrance. Coulomb and the Lennard-Jones interactions between CPZ and the ion channel as well as the conformational fluctuations of CPZ were examined to assess the contribution of each to the binding of CPZ to the nAChR. The MD simulations disclose a dynamic interaction of CPZ binding to the nAChR ionic channel. The cationic ammonium head of CPZ forms strong hydrogen bonds with Glu262 (alpha), Asp268 (beta), Glu272 (beta), Ser276 (beta), Glu280 (delta), Gln271 (gamma), Glu275 (gamma), and Asn279 (gamma) nAChR residues. Finally, the conventional MD simulation of CPZ at its identified binding site demonstrates that the binding of CPZ not only blocks ion transport through the channel but also markedly inhibits the conformational transitions of the channel, necessary for nAChR to carry out its biological function.