Open AccessCrystal Structure and Subsequent Ligand Design of a Nonriboside Partial Agonist Bound to the Adenosine A2A Receptor
Author(s) -
Tasia Amelia,
Jacobus P. D. van Veldhoven,
Matteo Falsini,
Ronghui Liu,
Laura H. Heitman,
Gerard J. P. van Westen,
Elena Segala,
Grégory Verdon,
R.K. Cheng,
Robert M. Cooke,
Adriaan P. IJzerman
Publication year - 2021
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.0c01856
Subject(s) - partial agonist , inverse agonist , agonist , chemistry , radioligand , ligand (biochemistry) , docking (animal) , adenosine , antagonist , stereochemistry , receptor , radioligand assay , adenosine receptor , biochemistry , medicine , nursing
In this study, we determined the crystal structure of an engineered human adenosine A 2A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists. We rationalized this remarkable behavior with additional computational docking studies.