Submission Date
Fall 2024
Abstract
The escalating global prevalence of nicotine addiction, particularly among younger populations, has been linked to the increasing use of e-cigarettes, commonly known as vapes. Approximately 1.63 million students (ages 11-18) currently use vapes, reflecting a concerning trend of nicotine dependence among adolescents. As the number of nicotine addiction cases continues to rise, the development of an anti-addiction drug market is evolving to address this urgent public health issue. One such treatment is varenicline that acts as a partial agonist at the α3β4 nicotine acetylcholine receptor nAChR, a key target for smoking cessation therapies. Activation of the 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 varenicline binding to the nAChR and explain nicotine dependence and withdrawal, specifically focusing on its interaction with subunits A and B of the pentameric receptor. This model highlights the binding of two competitive inhibitors, AT-1001 and varenicline, at the receptor’s orthostatic site located at the junction between subunits A and B. These ligands lessen the active conformation of the nicotinic receptor and reduce nicotine’s addictive potential by altering the receptor’s funnel-like structure to decrease dopamine release. The model elucidates key molecular interactions, including hydrogen bonds and hydrophobic contacts, with specific attention to important amino acids highlighted in the model's binding site. Using the application SwissDock, we found other medications (cytisine, bupropion, and mecamylamine) their binding affinity at the binding site between the A and B subunits of the α3β4 receptor. Analyzing the smoking cessation ligands’ chemical structures in correlation to their binding affinity, a proposed chemical drug that we named Fumerxia was modeled with an estimated binding affinity of -8.940 kcal/mol, significantly greater than its counterparts. Understanding the structural basis of varenicline on nAChR provides valuable insights into receptor modulation and lays the foundation for developing more effective and efficient treatments for nicotine addiction. This model shows the limited potential of varenicline's therapeutic impact and examines possible new drug interventions targeting nAChr-related smoking cessation and related disorders.
Recommended Citation
Madan, Japji; Cheong, Andersen; and Khandai, Mourya, "Modeling Nicotine, AT-1001, and Varenicline at the α3β4 Nicotine Acetylcholine Receptor" (2024). Protein Modeling Reports. 18.
https://nsuworks.nova.edu/protein_modeling_reports/18
Poster
Protein Modeling Proposal-Final.pdf (1788 kB)
Presentation