Molecular modeling studies of the nicotinic acetylcholine receptor (nAChRs) α4β2: Validation and analysis of bioactive compounds

The crystal structure of the nAChRs α4β2 was obtained from PDB (PDB ID: 5KXI). 3 The interactions between nicotine and the binding site residues were: W156 interacting with the pirrolidine basic nitrogen (pi-cation and backbone hydrogen bonding) and hydrophobic interactions with Y204, L121, T157, C199, C200, W57 and Y197. Docking parameters: explicit hydrogens, anhydrous binding site, rigid docking, ligand’s ionization state predicted by MarvinSuite for pH 7.4 and 50 docking poses. The choice of the scoring function was based on the lowest RMSD between heavy atoms of co-crystalized ligand and docked nicotine. ASP function yielded the best result, as shown in Table 1. Binding interactions for docked nicotine are represented in Figure 1. For the nicotinic ligands, the scoring function predicted interactions with the following key residues: W156 (100%), Y204 (86.7%), L121 (93.3%), T157 (30%), C199 (30%), C200 (96.7%), W57 (66.7%) and Y197 (30%). 10 out of 28 nicotinic ligands were predicted to be spatially oriented closely to what is observed for co-crystalized nicotine, as shown in Figure 2.