title: Homology modeling of human muscarinic acetylcholine receptors.
abstract: We have developed homology models of the acetylcholine muscarinic receptors M₁R-M₅R, based on the β₂-adrenergic receptor crystal as the template. This is the first report of homology modeling of all five subtypes of acetylcholine muscarinic receptors with binding sites optimized for ligand binding. The models were evaluated for their ability to discriminate between muscarinic antagonists and decoy compounds using virtual screening using enrichment factors, area under the ROC curve (AUC), and an early enrichment measure, LogAUC. The models produce rational binding modes of docked ligands as well as good enrichment capacity when tested against property-matched decoy libraries, which demonstrates their unbiased predictive ability. To test the relative effects of homology model template selection and the binding site optimization procedure, we generated and evaluated a naïve M₂R model, using the M₃R crystal structure as a template. Our results confirm previous findings that binding site optimization using ligand(s) active at a particular receptor, i.e. including functional knowledge into the model building process, has a more pronounced effect on model quality than target-template sequence similarity. The optimized M₁R-M₅R homology models are made available as part of the Supporting Information to allow researchers to use these structures, compare them to their own results, and thus advance the development of better modeling approaches.
authors: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade, Parkville, VIC 3052 Australia.
authors: Trayder
authors: T
authors: Thomas
authors: Kimberley C
authors: KC
authors: McLean
authors: Fiona M
authors: FM
authors: McRobb
authors: David T
authors: DT
authors: Manallack
authors: David K
authors: DK
authors: Chalmers
authors: Elizabeth
authors: E
authors: Yuriev
mesh_terms: D001665:Binding Sites; D019295:Computational Biology; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D018727:Muscarinic Antagonists / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism*; D012984:Software; D040681:Structural Homology, Protein; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D018727:Muscarinic Antagonists; D018343:Receptors, Adrenergic, beta-2; D011976:Receptors, Muscarinic