Abstract:

Three-dimensional structure model of M1 receptor was built through homology modeling. Mreceptor full agonist acetylcholine (ACh) and M1 receptor selective agonist xanomeline were docked into the model protein to form receptor-ligand complexes. Those complexes together with a receptor protein were put into a phospholipid bilayer for a 10 ns molecular dynamics (MD) simulation. Numbers of known active molecules were scattered into randomly selected databases, and the ACh compounds were docked with a model protein and ranked by their docking scores. The best model protein with the highest enrichment factor (EF) was chosen. The EF of the top5% of the active molecules for the chosen M1 protein receptor-xanomeline docking complex, the receptor-acetylcholine complex, and the non-complex were 8.0, 6.5, and 1.5, respectively. These results indicate that optimization of structures by MD simulation of M1 selective ligand-receptor is reasonable for virtual screening. The optimized M1 receptor protein structure can be used for virtual screening and for novel design to discover more potent compounds.

Key words: Molecular docking, M1 receptor, Homology modeling, Molecular dynamics