Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 243 - 253 |
| Number of pages | 11 |
| Journal | Journal of Chemical Information and Modeling |
| Volume | 54 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2014 |
Cite this
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Homology modeling of human muscarinic acetylcholine receptors. / Thomas, Trayder; McLean, Kimberley C; McRobb, Fiona Michelle; Manallack, David Thomas; Chalmers, David Kenneth; Yuriev, Elizabeth.
In: Journal of Chemical Information and Modeling, Vol. 54, No. 1, 2014, p. 243 - 253.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Homology modeling of human muscarinic acetylcholine receptors
AU - Thomas, Trayder
AU - McLean, Kimberley C
AU - McRobb, Fiona Michelle
AU - Manallack, David Thomas
AU - Chalmers, David Kenneth
AU - Yuriev, Elizabeth
PY - 2014
Y1 - 2014
N2 - We have developed homology models of the acetylcholine muscarinic receptors M1R-M5R, based on the ?2-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 naIve 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-M 5R 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.
AB - We have developed homology models of the acetylcholine muscarinic receptors M1R-M5R, based on the ?2-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 naIve 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-M 5R 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.
UR - http://pubs.acs.org/doi/pdf/10.1021/ci400502u
U2 - 10.1021/ci400502u
DO - 10.1021/ci400502u
M3 - Article
VL - 54
SP - 243
EP - 253
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
SN - 1549-9596
IS - 1
ER -