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I24-Microfocus Macromolecular Crystallography	X‐ray crystallography and free energy calculations reveal the binding mechanism of A2A adenosine receptor antagonists Willem Jespers , Gregory Verdon , Jhonny Azuaje , Maria Majellaro , Henrik Keränen , Xerardo García‐mera , Miles Congreve , Francesca Deflorian , Chris De Graaf , Andrei Zhukov , Andrew S. Dore , Jonathan S. Mason , Johan Åqvist , Robert M. Cooke , Eddy Sotelo , Hugo Gutiérrez‐de‐terán Angewandte Chemie International Edition DOI: 10.1002/anie.202003788 Diamond Proposal Number(s): [17185] Open Access Show Abstract ▼ 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.	Jul 2020

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I24-Microfocus Macromolecular Crystallography

X‐ray crystallography and free energy calculations reveal the binding mechanism of A2A adenosine receptor antagonists