Open AccessDesign of a True Bivalent Ligand with Picomolar Binding Affinity for a G Protein-Coupled Receptor Homodimer
Author(s) -
Daniel Pulido,
Verònica Casadó-Anguera,
Laura PérezBenito,
Estefanía Moreno,
Arnau Cordomí,
L. Madero López,
Antoni Cortés,
Sergi Ferré,
Leonardo Pardo,
Vicent Casadó,
Míriam Royo
Publication year - 2018
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.8b01249
Subject(s) - bivalent (engine) , chemistry , ligand (biochemistry) , stereochemistry , receptor , g protein coupled receptor , peptide , plasma protein binding , transmembrane protein , biophysics , biochemistry , biology , organic chemistry , metal
Bivalent ligands have emerged as chemical tools to study G protein-coupled receptor dimers. Using a combination of computational, chemical, and biochemical tools, here we describe the design of bivalent ligand 13 with high affinity ( K DB1 = 21 pM) for the dopamine D 2 receptor (D 2 R) homodimer. Bivalent ligand 13 enhances the binding affinity relative to monovalent compound 15 by 37-fold, indicating simultaneous binding at both protomers. Using synthetic peptides with amino acid sequences of transmembrane (TM) domains of D 2 R, we provide evidence that TM6 forms the interface of the homodimer. Notably, the disturber peptide TAT-TM6 decreased the binding of bivalent ligand 13 by 52-fold and had no effect on monovalent compound 15, confirming the D 2 R homodimer through TM6 ex vivo. In conclusion, by using a versatile multivalent chemical platform, we have developed a precise strategy to generate a true bivalent ligand that simultaneously targets both orthosteric sites of the D 2 R homodimer.