Exploring the binding site of the human muscarinic M3 receptor: Homology modeling and docking study

• Published in: International journal of quantum chemistry 2007, Vol.107 (8), p.1794-1802
• Main Authors: Ostopovici, Liliana, Mracec, Maria, Mracec, Mircea, Borota, Ana
• Format: Article
• Language: English
• Subjects: docking; homology modeling; human muscarinic M3 receptor; pharmacophore
• ISSN: 0020-7608; 1097-461X
• DOI: 10.1002/qua.21290

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 (Ψ) and psi (Φ) 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. © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2007