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Functional Probes of Drug−Receptor Interactions Implicated by Structural Studies: Cys-Loop Receptors Provide a Fertile Testing Ground

Van Arnam, Ethan B. and Dougherty, Dennis A. (2014) Functional Probes of Drug−Receptor Interactions Implicated by Structural Studies: Cys-Loop Receptors Provide a Fertile Testing Ground. Journal of Medicinal Chemistry, 57 (15). pp. 6289-6300. ISSN 0022-2623 . PMCID PMC4136689. http://resolver.caltech.edu/CaltechAUTHORS:20140401-153856294

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Abstract

Structures of integral membrane receptors provide valuable models for drug–receptor interactions across many important classes of drug targets and have become much more widely available in recent years. However, it remains to be determined to what extent these images are relevant to human receptors in their biological context and how subtle issues such as subtype selectivity can be informed by them. The high precision structural modifications enabled by unnatural amino acid mutagenesis on mammalian receptors expressed in vertebrate cells allow detailed tests of predictions from structural studies. Using the Cys-loop superfamily of ligand-gated ion channels, we show that functional studies lead to detailed binding models that, at times, are significantly at odds with the structural studies on related invertebrate proteins. Importantly, broad variations in binding interactions are seen for very closely related receptor subtypes and for varying drugs at a given binding site. These studies highlight the essential interplay between structural studies and functional studies that can guide efforts to develop new pharmaceuticals.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://pubs.acs.org/doi/abs/10.1021/jm500023mPublisherArticle
http://dx.doi.org/10.1021/jm500023mDOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136689/PubMed CentralArticle
ORCID:
AuthorORCID
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2014 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Publication Date (Web): February 25, 2014. Received: January 6, 2014. Our work in this area has been supported by the NIH and by the California Tobacco-Related Disease Research Program of the University of California.
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NIHUNSPECIFIED
California Tobacco-Related Disease Research ProgramUNSPECIFIED
PubMed Central ID:PMC4136689
Record Number:CaltechAUTHORS:20140401-153856294
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20140401-153856294
Official Citation:Functional Probes of Drug–Receptor Interactions Implicated by Structural Studies: Cys-Loop Receptors Provide a Fertile Testing Ground Ethan B. Van Arnam and Dennis A. Dougherty Journal of Medicinal Chemistry 2014 57 (15), 6289-6300
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44594
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:01 Apr 2014 22:52
Last Modified:21 Jul 2017 18:08

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