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X-Ray Crystallograp...
X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A(2A) Adenosine Receptor Antagonists
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- Jespers, Willem (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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- Verdon, Gregory (author)
- Sosei Heptares, Steinmetz Granta Pk, Cambridge CB21 6DG, England.
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- Azuaje, Jhonny (author)
- Univ Santiago de Compostela, Fac Farmacy, Dept Organ Chem, Santiago De Compostela, Spain.;Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela, Spain.
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- Majellaro, Maria (author)
- Univ Santiago de Compostela, Fac Farmacy, Dept Organ Chem, Santiago De Compostela, Spain.;Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela, Spain.
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- Keränen, Henrik, 1983- (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi,Uppsala Univ, Biomed Ctr, Dept Cell & Mol Biol, BMC, Box 596, Uppsala, Sweden.;H Lundbeck & Co AS, Ottiliavej 9, DK-2500 Valby, Denmark.
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- Garcia-Mera, Xerardo (author)
- Univ Santiago de Compostela, Fac Farmacy, Dept Organ Chem, Santiago De Compostela, Spain.
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- Congreve, Miles (author)
- Sosei Heptares, Steinmetz Granta Pk, Cambridge CB21 6DG, England.
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- Deflorian, Francesca (author)
- Sosei Heptares, Steinmetz Granta Pk, Cambridge CB21 6DG, England.
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- de Graaf, Chris (author)
- Sosei Heptares, Steinmetz Granta Pk, Cambridge CB21 6DG, England.
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- Zhukov, Andrei (author)
- Sosei Heptares, Steinmetz Granta Pk, Cambridge CB21 6DG, England.
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- Dore, Andrew S. (author)
- Sosei Heptares, Steinmetz Granta Pk, Cambridge CB21 6DG, England.
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- Mason, Jonathan S. (author)
- Sosei Heptares, Steinmetz Granta Pk, Cambridge CB21 6DG, England.
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- Åqvist, Johan (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Beräkningsbiologi och bioinformatik
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- Cooke, Robert M. (author)
- Sosei Heptares, Steinmetz Granta Pk, Cambridge CB21 6DG, England.
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- Sotelo, Eddy (author)
- Univ Santiago de Compostela, Fac Farmacy, Dept Organ Chem, Santiago De Compostela, Spain.;Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela, Spain.
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- Gutiérrez-de-Terán, Hugo (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2020-07-22
- 2020
- English.
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In: Angewandte Chemie International Edition. - : WILEY-V C H VERLAG GMBH. - 1433-7851 .- 1521-3773. ; 59:38, s. 16536-16543
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Abstract
Subject headings
Close
- 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.
Subject headings
- NATURVETENSKAP -- Kemi -- Organisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Organic Chemistry (hsv//eng)
- NATURVETENSKAP -- Kemi -- Teoretisk kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Theoretical Chemistry (hsv//eng)
Keyword
- adenosine receptors
- biophysical mapping (BPM)
- free energy perturbation (FEP)
- G protein-coupled receptor (GPCR)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Jespers, Willem
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Verdon, Gregory
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Azuaje, Jhonny
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Majellaro, Maria
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Keränen, Henrik, ...
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Garcia-Mera, Xer ...
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show more...
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Congreve, Miles
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Deflorian, Franc ...
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de Graaf, Chris
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Zhukov, Andrei
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Dore, Andrew S.
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Mason, Jonathan ...
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Åqvist, Johan
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Cooke, Robert M.
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Sotelo, Eddy
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Gutiérrez-de-Ter ...
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Organic Chemistr ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Chemical Science ...
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and Theoretical Chem ...
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Angewandte Chemi ...
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Uppsala University