Drugs for allosteric sites on receptors

Cody J. Wenthur, Patrick R. Gentry, Thomas P. Mathews, Craig W. Lindsley

Research output: Contribution to journalReview articlepeer-review

181 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)165-184
Number of pages20
JournalAnnual review of pharmacology and toxicology
StatePublished - Jan 2014
Externally publishedYes


  • Drug discovery
  • G protein-coupled receptors
  • GPCRs
  • Kinases
  • Molecular switch
  • Phospholipases
  • SAR
  • Structure-activity relationship

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology


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