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Similarity- and substructure-based development of β2-adrenergic receptor ligands based on unusual scaffolds

Schmidt, Denis; Gunera, Jakub; Baker, Jillian G.; Kolb, Peter

Authors

Denis Schmidt

Jakub Gunera

JILLIAN BARKER jillian.baker@nottingham.ac.uk
Professor of Drug Discovery and Respiratory Medicine

Peter Kolb



Abstract

The β2-adrenergic receptor (β2AR) is a G protein-coupled receptor (GPCR) and a well-explored target. Here, we report the discovery of 13 ligands, ten of which are novel, of this particular GPCR. They have been identified by similarity- and substructure-based searches using multiple ligands, which were described in an earlier study, as starting points. Of note, two of the molecules used as queries here distinguish themselves from other β2AR antagonists by their unique scaffold. The molecules described in this work allow us to explore the ligand space around the previously reported molecules in greater detail, leading to insights into their structure−activity relationship. We also report experimental binding and selectivity data and putative binding modes for the novel molecules.

Journal Article Type Article
Journal ACS Medicinal Chemistry Letters
Print ISSN 1948-5875
Electronic ISSN 1948-5875
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
APA6 Citation Schmidt, D., Gunera, J., Baker, J. G., & Kolb, P. (in press). Similarity- and substructure-based development of β2-adrenergic receptor ligands based on unusual scaffolds. ACS Medicinal Chemistry Letters, https://doi.org/10.1021/acsmedchemlett.6b00363
DOI https://doi.org/10.1021/acsmedchemlett.6b00363
Keywords Docking; SAR-by-catalog; Similarity searches; β2-adrenergic receptor
Publisher URL http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00363
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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letterb2ar_proof_MS.jb.jg.ds.pdf (1.1 Mb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf


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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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