X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A 2A Adenosine Receptor Antagonists
| Autor: | María Majellaro, Robert M. Cooke, Andrei Zhukov, Andrew S. Doré, Francesca Deflorian, Henrik Keränen, Hugo Gutiérrez-de-Terán, Grégory Verdon, Miles Congreve, Johan Åqvist, Eddy Sotelo, Jhonny Azuaje, Xerardo García-Mera, Chris de Graaf, Willem Jespers, Jonathan S. Mason |
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| Přispěvatelé: | Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares, Universidade de Santiago de Compostela. Departamento de Química Orgánica |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Receptor Adenosine A2A Receptor Binding G protein-coupled receptor (GPCR) free energy perturbation (FEP) Crystallography X-Ray 010402 general chemistry 01 natural sciences Catalysis Humans Adenosine receptors Biophysical mapping (BPM) Research Articles Binding Sites Molecular Structure 010405 organic chemistry Chemistry biophysical mapping (BPM) General Chemistry Adenosine receptor adenosine receptors 0104 chemical sciences Crystallography Purinergic P1 Receptor Antagonists X-ray crystallography Thermodynamics Free energy perturbation (FEP) Mechanism (sociology) Research Article |
| Zdroj: | Angewandte Chemie (International Ed. in English) Minerva: Repositorio Institucional de la Universidad de Santiago de Compostela Universidad de Santiago de Compostela (USC) Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname |
| ISSN: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.202003788 |
| Popis: | 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. In molecular design, structural, pharmacological and chemical information can be interconnected by computational estimations of binding free energies. Using a combined FEP approach to examine both mutagenesis and ligand SAR, we designed new analogues of the A2AAR antagonist series of chromones. Subsequent crystal structures supported the rational design of these compounds, linking the structural and energetic understanding on ligand binding. |
| Databáze: | OpenAIRE |
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