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X‐ray crystallography and free energy calculations reveal the binding mechanism of A2A adenosine receptor antagonists
Authors:
Willem
Jespers
(Uppsala University)
,
Gregory
Verdon
(Sosei Heptares)
,
Jhonny
Azuaje
(Universidade de Santiago de Compostela)
,
Maria
Majellaro
(Universidade de Santiago de Compostela)
,
Henrik
Keränen
(Uppsala University)
,
Xerardo
García‐mera
(Universidade de Santiago de Compostela)
,
Miles
Congreve
(Sosei Heptares)
,
Francesca
Deflorian
(Sosei Heptares)
,
Chris
De Graaf
(Sosei Heptares)
,
Andrei
Zhukov
(Sosei Heptares)
,
Andrew S.
Dore
(Sosei Heptares)
,
Jonathan S.
Mason
(Sosei Heptares)
,
Johan
Åqvist
(Uppsala University)
,
Robert M.
Cooke
(Sosei Heptares)
,
Eddy
Sotelo
(Universidade de Santiago de Compostela)
,
Hugo
Gutiérrez‐de‐terán
(Uppsala University)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Angewandte Chemie International Edition
State:
Published (Approved)
Published:
July 2020
Diamond Proposal Number(s):
17185

Abstract: 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 A2A adenosine receptor (AR). Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed 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 ligand‐FEP 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.
Journal Keywords: adenosine receptors; biophysical mapping (BPM); free energy perturbation (FEP); G protein-coupled receptor (GPCR)
Subject Areas:
Chemistry,
Biology and Bio-materials,
Medicine
Instruments:
I24-Microfocus Macromolecular Crystallography
Added On:
21/09/2020 14:23
Documents:
anie.202003788.pdf
Discipline Tags:
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Biophysics
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)