Homology modeling and docking evaluation of human muscarinic acetylcholine receptors

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Abstract

The development of GPCR homology models for virtual screening is an active area of research. Here we describe methods for homology modeling of the acetylcholine muscarinic receptors M1R–M5R. The models are based on the β2-adrenergic receptor crystal structure as the template and binding sites are optimized for ligand binding. An important aspect of homology modeling is the evaluation of the models for their ability to discriminate between active compounds and (presumed) inactive decoy compounds by virtual screening. The predictive ability is quantified using enrichment factors, area under the ROC curve (AUC), and an early enrichment measure, LogAUC. The models produce good enrichment capacity, which demonstrates their unbiased predictive ability. The optimized M1R–M5R homology models have been made freely available to the scientific community to allow researchers to use these structures, compare them to their results, and thus advance the development of better modeling approaches.
Original languageEnglish
Title of host publicationMuscarinic Receptor: From Structure to Animal Models
EditorsJaromir Myslivecek, Jan Jakubik
Place of PublicationNew York NY USA
PublisherSpringer
Pages15-35
Number of pages21
Volume107
ISBN (Electronic)9781493928583
ISBN (Print)9781493928576
DOIs
Publication statusPublished - 2016

Publication series

NameNeuromethods
PublisherSpringer
ISSN (Print)0893-2336
ISSN (Electronic)1940-6045

Keywords

  • Acetylcholine muscarinic receptor
  • Binding site optimization
  • Decoy
  • Docking
  • GPCR
  • Homology modeling
  • Virtual screening

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