Homology Modeling of Human Muscarinic Acetylcholine Receptors

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 naı̈ve 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.