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ABSTRACT:The human muscarinic M3 receptor (hM3) and its interactions with selective agonists and antagonists were investigated by means of combined homology and docking approach. Also, two pharmacophoric models for the hM3 agonist and antagonist binding sites were proposed. The three-dimensional (3D) structure of hM3 receptor was modeled based on the high-resolution X-ray structure of bovine rhodopsin from the Protein Data Bank (PDB). To validate the reliability of the model obtained, the main chain torsion angles phi (⌿ ) and psi (⌽) were examined in a Ramachandran plot, and all omega angles were measured for peptidic bond planarity. The characteristics of the active site, the position, and the orientation of ligands in situ, as well as the binding modes of the representative agonists and antagonists, were analyzed by applying a molecular docking technique using the AutoDock 3.0.5 program. Specific interactions responsible for recognition of the hM3 receptor, like ionic bond formed between protonated amine of the ligands and the Asp3.6 side chain were identified. Structure-reactivity relationships have been explained by analyzing the 3D structure of the hM3 model and the ligand conformations resulted from molecular docking simulation.

A conformational search in vacuum for a series of 1,3-substituted pyrrolidine derivatives has been performed using the AMBER, AM1, PM3, and MNDO methods. Conformational analysis of the pyrrolidine ligands suggests that these compounds could have many conformers that populate the low-energy minima on the potential energy surface (PES). The conformational space occupied by the ligands is large and, in vacuum, the rotation barriers of different flexible bonds have energies between 0.5 and thousands of kcal/mol. By optimization, most conformers have energy barriers of 0 -5 kcal/mol; thus, they could interconvert easily to obtain better interactions in the receptor active site. Optimized conformers having energy barriers of Ͼ5 kcal/mol display bad geometries with very large bond lengths and deformed rings. Shapes and heights of rotation barriers obtained through COSMO-AM1 single-point calculations in water are similar to those obtained from single-point calculations in vacuum. However, in water the energy barriers are lower, allowing most conformers to convert in other low-energy conformers. The best conformers in vacuum and in water are different: the gas phase best conformer has a helical shape, while the best conformer in water has an extended shape.