J Chem Inf Model - Homology modeling of human muscarinic acetylcholine receptors.

Tópicos

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Resumo

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 na?ve 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.

Resumo Limpo

develop homolog model acetylcholin muscarin receptor mrmr base adrenerg receptor crystal templat first report homolog model five subtyp acetylcholin muscarin receptor bind site optim ligand bind model evalu abil discrimin muscarin antagonist decoy compound use virtual screen use enrich factor area roc curv auc earli enrich measur logauc model produc ration bind mode dock ligand well good enrich capac test propertymatch decoy librari demonstr unbias predict abil test relat effect homolog model templat select bind site optim procedur generat evalu nave mr model use mr crystal structur templat result confirm previous find bind site optim use ligand activ particular receptor ie includ function knowledg model build process pronounc effect model qualiti targettempl sequenc similar optim mrmr homolog model made avail part support inform allow research use structur compar result thus advanc develop better model approach

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