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 - 2014/1
Y1 - 2014/1
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
SN - 0362-1642
VL - 54
SP - 165
EP - 184
JO - Annual Review of Pharmacology and Toxicology
JF - Annual Review of Pharmacology and Toxicology
ER -