X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A 2A Adenosine Receptor Antagonists.

Autor: Jespers W; Department of Cell and Molecular Biology, Uppsala University, BMC, Biomedical Center, Box 596, Uppsala, Sweden., Verdon G; Sosei Heptares, Steinmetz Granta Park, Great Abington, Cambridge, CB21 6DG, UK., Azuaje J; Departament of Organic Chemistry, Faculty of Farmacy, Universidade de Santiago de Compostela, Spain.; Centro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, Spain., Majellaro M; Departament of Organic Chemistry, Faculty of Farmacy, Universidade de Santiago de Compostela, Spain.; Centro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, Spain., Keränen H; Department of Cell and Molecular Biology, Uppsala University, BMC, Biomedical Center, Box 596, Uppsala, Sweden.; Present address: H. Lundbeck A/S, Ottiliavej 9, 2500, Valby, Denmark., García-Mera X; Departament of Organic Chemistry, Faculty of Farmacy, Universidade de Santiago de Compostela, Spain., Congreve M; Sosei Heptares, Steinmetz Granta Park, Great Abington, Cambridge, CB21 6DG, UK., Deflorian F; Sosei Heptares, Steinmetz Granta Park, Great Abington, Cambridge, CB21 6DG, UK., de Graaf C; Sosei Heptares, Steinmetz Granta Park, Great Abington, Cambridge, CB21 6DG, UK., Zhukov A; Sosei Heptares, Steinmetz Granta Park, Great Abington, Cambridge, CB21 6DG, UK., Doré AS; Sosei Heptares, Steinmetz Granta Park, Great Abington, Cambridge, CB21 6DG, UK., Mason JS; Sosei Heptares, Steinmetz Granta Park, Great Abington, Cambridge, CB21 6DG, UK., Åqvist J; Department of Cell and Molecular Biology, Uppsala University, BMC, Biomedical Center, Box 596, Uppsala, Sweden., Cooke RM; Sosei Heptares, Steinmetz Granta Park, Great Abington, Cambridge, CB21 6DG, UK., Sotelo E; Departament of Organic Chemistry, Faculty of Farmacy, Universidade de Santiago de Compostela, Spain.; Centro Singular de Investigación en Química Biolóxica y Materiais Moleculares (CIQUS), Universidade de Santiago de Compostela, Spain., Gutiérrez-de-Terán H; Department of Cell and Molecular Biology, Uppsala University, BMC, Biomedical Center, Box 596, Uppsala, Sweden.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2020 Sep 14; Vol. 59 (38), pp. 16536-16543. Date of Electronic Publication: 2020 Jul 22.
DOI: 10.1002/anie.202003788
Abstrakt: 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 immuno-oncology.
(© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)
Databáze: MEDLINE
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