Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 38, Pages 16536-16543Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202003788
Keywords
adenosine receptors; biophysical mapping (BPM); free energy perturbation (FEP); G protein-coupled receptor (GPCR)
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Funding
- Swedish Research Council [521-2014-2118]
- Conselleria de Cultura, Educacion e Ordenacion Universitaria of the Galician Government [ED431B2017/70]
- Centro Singular de Investigacion de Galicia accreditation 2016-2019 [ED431G/09]
- European Regional Development Fund (ERDF)
- Swedish strategic research program eSSENCE
- European COST action ERNEST [CA 18133]
- European COST action GLISTEN [CA 1207]
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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 A(2A) adenosine receptor (AR). Eight A(2A)AR 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 A(2A)AR 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 A(2A)AR 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 A(2A)AR, an emerging target in immunooncology.
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