Computational modeling study of human nicotinic acetylcholine receptor for developing new drugs in the treatment of alcoholism.

Alcohol abuse and alcoholism are serious and costly problem in USA. Thus, the development of anti-alcoholism agents could be very significant. The understanding of the neurochemical basis underlying the addictive properties of drugs of abuse is imperative for the development of new pharmacological means to reverse the addictive state, prevent relapse or to reduce the intake of addictive compounds. The nicotinic acetylcholine receptors (nAChRs) are important therapeutic targets for various diseases. Recent studies have revealed that the alpha3beta2, alpha3beta3, and alpha6 subunits of nAChR protein family might be pharmacological targets for developing new drugs in the treatment of alcoholism. We have performed computational homology modeling of the alpha3beta2, alpha3beta3, and alpha6 subunits of human nACHRs based upon the recently determined crystal structure of the extracellular domain (ECD) of the mouse nAChR alpha1 subunit complexed with alpha-bungarotoxin at 1.94 A resolution. For comparison, we also built the ECD models of alpha4beta2, and alpha7 subunits of human nACHRs which are neurochemical targets for cessation of smoking. The three-dimensional (3D) models of the ECD of the monomer, and pentamer of these human nAChR were constructed. The docking of the agonist in the ligand-binding pocket of the human nAChR dimers was also performed. Since the nAChR ligand-binding site is a useful target for mutagenesis studies and the rational design of drugs against various diseases, these models provide useful information for future investigation.