Homology modeling of human muscarinic acetylcholine receptors

Trayder Thomas, Kimberley C McLean, Fiona Michelle McRobb, David Thomas Manallack, David Kenneth Chalmers, Elizabeth Yuriev

Research output: Contribution to journalArticleResearchpeer-review

13 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)243 - 253
Number of pages11
JournalJournal of Chemical Information and Modeling
Volume54
Issue number1
DOIs
Publication statusPublished - 2014

Cite this

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title = "Homology modeling of human muscarinic acetylcholine receptors",
abstract = "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.",
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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 journalArticleResearchpeer-review

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AU - Manallack, David Thomas

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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.

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