Drugs for allosteric sites on receptors

Research output: Contribution to journalReviewResearchpeer-review

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

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
JournalAnnual Review of Pharmacology and Toxicology
Volume54
Pages (from-to)165-84
Number of pages20
ISSN0362-1642
DOIs
Publication statusPublished - 2014
Externally publishedYes

    Research areas

  • Allosteric Regulation/drug effects, Allosteric Site/drug effects, Drug Design, Humans, Ligands, Pharmaceutical Preparations/metabolism, Receptors, G-Protein-Coupled/metabolism, Signal Transduction, Structure-Activity Relationship

ID: 213599881