TY - JOUR

T1 - Drugs for allosteric sites on receptors

AU - Wenthur, Cody J

AU - Gentry, Patrick R

AU - Mathews, Thomas P

AU - Lindsley, Craig W

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Allosteric Regulation/drug effects

KW - Allosteric Site/drug effects

KW - Drug Design

KW - Humans

KW - Ligands

KW - Pharmaceutical Preparations/metabolism

KW - Receptors, G-Protein-Coupled/metabolism

KW - Signal Transduction

KW - Structure-Activity Relationship

U2 - 10.1146/annurev-pharmtox-010611-134525

DO - 10.1146/annurev-pharmtox-010611-134525

M3 - Review

C2 - 24111540

VL - 54

SP - 165

EP - 184

JO - Annual Review of Pharmacology and Toxicology

JF - Annual Review of Pharmacology and Toxicology

SN - 0362-1642

ER -