Journal
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 54
Volume 54, Issue -, Pages 165-184Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-010611-134525
Keywords
G protein-coupled receptors; GPCRs; kinases; phospholipases; molecular switch; drug discovery; structure-activity relationship; SAR
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Funding
- NIGMS NIH HHS [T32 GM007628] Funding Source: Medline
- NIMH NIH HHS [T32 MH093366] Funding Source: Medline
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The presence of druggable, topographically distinct allosteric sites on a wide range of receptor families has offered new paradigms for small molecules to modulate receptor function. Moreover, ligands that target allosteric sites offer significant advantages over the corresponding orthosteric ligands in terms of selectivity, including subtype selectivity within receptor families, and can also impart improved physicochemical properties. However, allosteric ligands are not a panacea. Many chemical issues (e.g., flat structure-activity relationships) and pharmacological issues (e.g., ligand-biased signaling) that are allosteric centric have emerged. Notably, the fact that allosteric sites are less evolutionarily conserved leads to improved selectivity; however, this can also lead to species differences that can hinder safety assessment. Many allosteric ligands possess molecular switches, wherein a small structural change (chemical or metabolic) can modulate the mode of pharmacology or receptor subtype selectivity. As the field has matured, as described here, key principles and strategies have emerged for the design of ligands/drugs for allosteric sites.
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