NDLI: Computational studies to predict or explain GPCR polypharmacology

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Computational studies to predict or explain GPCR polypharmacology

Content Provider	PubMed Central
Author	Jacobson, Kenneth A. Costanzi, Stefano Paoletta, Silvia
Abstract	Since G protein-coupled receptors (GPCRs) belong to a very large superfamily of evolutionarily related receptors (>800 members in the human) and due to the rapid progress on their structural biology, they are ideal candidates for polypharmacology studies. Broad screening and bioinformatics/chemoinformatics have been applied to understanding off-target effects of GPCR ligands. It is now feasible to approach the question of GPCR polypharmacology using molecular modeling and the available X-ray GPCR structures. As an example, large and sterically constrained adenosine derivatives (potent adenosine receptor ligands with low conformational freedom and multiple extended substituents) were screened in binding at diverse receptors. Unanticipated off-target interactions, including at biogenic amine receptors, were then modeled using a structure-based approach to provide a consistent understanding of recognition. A conserved Asp in TM3 changed its role from counterion for biogenic amines to characteristic H-bonding to adenosine. The same systematic approach could potentially be applied to many GPCRs or other receptors using other sets of congeneric ligands.
Related Links	http://dx.doi.org/10.1016/j.tips.2014.10.009
Ending Page	663
Page Count	6
Starting Page	658
File Format	PDF
ISSN	01656147
e-ISSN	18733735
Journal	Trends in pharmacological sciences
Issue Number	12
Volume Number	35
Language	English
Publisher Date	2014-12-01
Access Restriction	Open
Subject Keyword	Toxicology Pharmacology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Toxicology Pharmacology

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