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Ligand design by targeting a binding site water

Solvent reorganization is a major driving force of protein–ligand association, but the contribution of binding site waters to ligand affinity is poorly understood. We investigated how altered interactions with a water network can influence ligand binding to a receptor. A series of ligands of the A(2...

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Autores principales: Matricon, Pierre, Suresh, R. Rama, Gao, Zhan-Guo, Panel, Nicolas, Jacobson, Kenneth A., Carlsson, Jens
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179138/
https://www.ncbi.nlm.nih.gov/pubmed/34163862
http://dx.doi.org/10.1039/d0sc04938g
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author Matricon, Pierre
Suresh, R. Rama
Gao, Zhan-Guo
Panel, Nicolas
Jacobson, Kenneth A.
Carlsson, Jens
author_facet Matricon, Pierre
Suresh, R. Rama
Gao, Zhan-Guo
Panel, Nicolas
Jacobson, Kenneth A.
Carlsson, Jens
author_sort Matricon, Pierre
collection PubMed
description Solvent reorganization is a major driving force of protein–ligand association, but the contribution of binding site waters to ligand affinity is poorly understood. We investigated how altered interactions with a water network can influence ligand binding to a receptor. A series of ligands of the A(2A) adenosine receptor, which either interacted with or displaced an ordered binding site water, were studied experimentally and by molecular dynamics simulations. An analog of the endogenous ligand that was unable to hydrogen bond to the ordered water lost affinity and this activity cliff was captured by molecular dynamics simulations. Two compounds designed to displace the ordered water from the binding site were then synthesized and evaluated experimentally, leading to the discovery of an A(2A) agonist with nanomolar activity. Calculation of the thermodynamic profiles resulting from introducing substituents that interacted with or displaced the ordered water showed that the gain of binding affinity was enthalpy driven. Detailed analysis of the energetics and binding site hydration networks revealed that the enthalpy change was governed by contributions that are commonly neglected in structure-based drug optimization. In particular, simulations suggested that displacement of water from a binding site to the bulk solvent can lead to large energy contributions. Our findings provide insights into the molecular driving forces of protein–ligand binding and strategies for rational drug design.
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spelling pubmed-81791382021-06-22 Ligand design by targeting a binding site water Matricon, Pierre Suresh, R. Rama Gao, Zhan-Guo Panel, Nicolas Jacobson, Kenneth A. Carlsson, Jens Chem Sci Chemistry Solvent reorganization is a major driving force of protein–ligand association, but the contribution of binding site waters to ligand affinity is poorly understood. We investigated how altered interactions with a water network can influence ligand binding to a receptor. A series of ligands of the A(2A) adenosine receptor, which either interacted with or displaced an ordered binding site water, were studied experimentally and by molecular dynamics simulations. An analog of the endogenous ligand that was unable to hydrogen bond to the ordered water lost affinity and this activity cliff was captured by molecular dynamics simulations. Two compounds designed to displace the ordered water from the binding site were then synthesized and evaluated experimentally, leading to the discovery of an A(2A) agonist with nanomolar activity. Calculation of the thermodynamic profiles resulting from introducing substituents that interacted with or displaced the ordered water showed that the gain of binding affinity was enthalpy driven. Detailed analysis of the energetics and binding site hydration networks revealed that the enthalpy change was governed by contributions that are commonly neglected in structure-based drug optimization. In particular, simulations suggested that displacement of water from a binding site to the bulk solvent can lead to large energy contributions. Our findings provide insights into the molecular driving forces of protein–ligand binding and strategies for rational drug design. The Royal Society of Chemistry 2020-11-19 /pmc/articles/PMC8179138/ /pubmed/34163862 http://dx.doi.org/10.1039/d0sc04938g Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/
spellingShingle Chemistry
Matricon, Pierre
Suresh, R. Rama
Gao, Zhan-Guo
Panel, Nicolas
Jacobson, Kenneth A.
Carlsson, Jens
Ligand design by targeting a binding site water
title Ligand design by targeting a binding site water
title_full Ligand design by targeting a binding site water
title_fullStr Ligand design by targeting a binding site water
title_full_unstemmed Ligand design by targeting a binding site water
title_short Ligand design by targeting a binding site water
title_sort ligand design by targeting a binding site water
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179138/
https://www.ncbi.nlm.nih.gov/pubmed/34163862
http://dx.doi.org/10.1039/d0sc04938g
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