Modeling Nicotine, AT-1001, & Varenicline at the α3β4 Nicotine Acetylcholine Receptor

Modeling Nicotine, AT-1001, & Varenicline at the α3β4 Nicotine Acetylcholine Receptor

Alvin Sherman Library

The escalating prevalence of nicotine addiction among adolescents has been linked to the increasing use of e-cigarettes, known as vapes. Approximately, 1.63 million students in the United States (ages 11-18) use vapes, reflecting a concerning trend of nicotine dependence among adolescents. Activation of the nicotine acetylcholine receptor (nAChR) can modulate the dopamine pathways in the mesolimbic system, increasing nicotine addictive behavior. A 3-D printed molecular model was prepared using the PDB file 6PV7, to explore the molecular dynamics of one of the binding sites between subunits A and B of the pentameric receptor. This model highlights the binding of two competitive inhibitors, AT-1001 antagonist and Varenicline, an antiaddiction drug, at the receptor’s binding site. The model elucidates key molecular interactions including hydrogen bonds, hydrophobic contacts, and important amino acids highlighted at the model's binding site. Using the application SwissDock we found other medications (Cytisine, Bupropion, and Mecamylamine) were tested for their binding affinity at the binding site. Analyzing the medications ligands’ chemical structures and binding affinities, we proposed a chemical drug named Fumerexia. Fumerexia has a higher binding affinity of - 8.940 kcal/mol, increasing its potential effectiveness to inhibit the nAChR. Understanding the structural basis of varenicline and other medications on nAChR provides valuable insights into receptor modulation and the foundation for developing more effective treatments for nicotine addiction. This model shows the limited potential of Varenicline's therapeutic impact and explores a possible new drug targeting nAChr-related smoking cessation.