RT Journal Article
T1 X-Ray crystallography and free energy calculations reveal the binding mechanism of A2A adenosine receptor antagonists
A1 Jespers, Willem
A1 Verdon, Grégory
A1 Azuaje, Jhonny
A1 Majellaro, María
A1 Keränen, Henrik
A1 García Mera, Xerardo
A1 Congreve, Miles
A1 Deflorian, Francesca
A1 De Graaf, Chris
A1 Zhukov, Andrey
A1 Doré, Andrew S.
A1 Mason, Jonathan S.
A1 Åqvist, Johan
A1 Cooke, Robert M.
A1 Sotelo Pérez, Eddy
A1 Gutiérrez de Terán, Hugo
K1 Adenosine receptors
K1 Biophysical mapping (BPM)
K1 Free energy perturbation (FEP)
K1 G protein-coupled receptor (GPCR)
AB We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X-ray crystallography to reveal the binding mode of an antagonist series to the adenosine A2A receptor (AR).Eight A2AAR binding site mutations from biophisical mapping experiments were initially analysed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2AAR were experimentally determined and investigated through a cycle of ligandFEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X-ray crystallography of the A2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2AAR, an emerging target in immuno-oncology.
PB Wiley-VCH
YR 2020
FD 2020
LK http://hdl.handle.net/10347/32497
UL http://hdl.handle.net/10347/32497
LA eng
NO Jespers, W., Verdon, G., Azuaje, J., Majellaro, M., Keränen, H., García-Mera, X., Congreve, M., Deflorian, F., de Graaf, C., Zhukov, A., Doré, A.S., Mason, J.S., Åqvist, J., Cooke, R.M., Sotelo, E., Gutiérrez-de-Terán, H. (2020). X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists. "Angewandte Chemie International Edition", vol. 59, 16536-16553
NO This work was financially supported by the Swedish Research Council; Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government (GrantED431B2017/70); Centro Singular de Investigación de Galicia accreditation 2016–2019 (Grant ED431G/09), and the European Regional Development Fund (ERDF). Additional support from the Swedish strategic research program eSSENCE is acknowledged. The computations were performed on resources provided by the Swedish National Infrastructure for Computing (SNIC). This research program has been developed in the frame of the European COST action ERNEST (Grant CA 18133) and GLISTEN (Grant CA 1207).
DS Minerva
RD 28 abr 2026