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Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics

The exchange proteins activated by cAMP (EPAC) are implicated in a large variety of physiological processes and they are considered as promising targets for a wide range of therapeutic applications. Several recent reports provided evidence for the therapeutic effectiveness of the inhibiting EPAC1 ac...

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Autores principales: Bufano, Marianna, Laudette, Marion, Blondeau, Jean-Paul, Lezoualc’h, Frank, Nalli, Marianna, Silvestri, Romano, Brancale, Andrea, Coluccia, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533256/
https://www.ncbi.nlm.nih.gov/pubmed/32700175
http://dx.doi.org/10.1007/s10822-020-00332-y
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author Bufano, Marianna
Laudette, Marion
Blondeau, Jean-Paul
Lezoualc’h, Frank
Nalli, Marianna
Silvestri, Romano
Brancale, Andrea
Coluccia, Antonio
author_facet Bufano, Marianna
Laudette, Marion
Blondeau, Jean-Paul
Lezoualc’h, Frank
Nalli, Marianna
Silvestri, Romano
Brancale, Andrea
Coluccia, Antonio
author_sort Bufano, Marianna
collection PubMed
description The exchange proteins activated by cAMP (EPAC) are implicated in a large variety of physiological processes and they are considered as promising targets for a wide range of therapeutic applications. Several recent reports provided evidence for the therapeutic effectiveness of the inhibiting EPAC1 activity cardiac diseases. In that context, we recently characterized a selective EPAC1 antagonist named AM-001. This compound was featured by a non-competitive mechanism of action but the localization of its allosteric site to EPAC1 structure has yet to be investigated. Therefore, we performed cosolvent molecular dynamics with the aim to identify a suitable allosteric binding site. Then, the docking and molecular dynamics were used to determine the binding of the AM-001 to the regions highlighted by cosolvent molecular dynamics for EPAC1. These analyses led us to the identification of a suitable allosteric AM-001 binding pocket at EPAC1. As a model validation, we also evaluated the binding poses of the available AM-001 analogues, with a different biological potency. Finally, the complex EPAC1 with AM-001 bound at the putative allosteric site was further refined by molecular dynamics. The principal component analysis led us to identify the protein motion that resulted in an inactive like conformation upon the allosteric inhibitor binding. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10822-020-00332-y) contains supplementary material, which is available to authorized users.
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spelling pubmed-75332562020-10-19 Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics Bufano, Marianna Laudette, Marion Blondeau, Jean-Paul Lezoualc’h, Frank Nalli, Marianna Silvestri, Romano Brancale, Andrea Coluccia, Antonio J Comput Aided Mol Des Article The exchange proteins activated by cAMP (EPAC) are implicated in a large variety of physiological processes and they are considered as promising targets for a wide range of therapeutic applications. Several recent reports provided evidence for the therapeutic effectiveness of the inhibiting EPAC1 activity cardiac diseases. In that context, we recently characterized a selective EPAC1 antagonist named AM-001. This compound was featured by a non-competitive mechanism of action but the localization of its allosteric site to EPAC1 structure has yet to be investigated. Therefore, we performed cosolvent molecular dynamics with the aim to identify a suitable allosteric binding site. Then, the docking and molecular dynamics were used to determine the binding of the AM-001 to the regions highlighted by cosolvent molecular dynamics for EPAC1. These analyses led us to the identification of a suitable allosteric AM-001 binding pocket at EPAC1. As a model validation, we also evaluated the binding poses of the available AM-001 analogues, with a different biological potency. Finally, the complex EPAC1 with AM-001 bound at the putative allosteric site was further refined by molecular dynamics. The principal component analysis led us to identify the protein motion that resulted in an inactive like conformation upon the allosteric inhibitor binding. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10822-020-00332-y) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-07-22 2020 /pmc/articles/PMC7533256/ /pubmed/32700175 http://dx.doi.org/10.1007/s10822-020-00332-y Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Bufano, Marianna
Laudette, Marion
Blondeau, Jean-Paul
Lezoualc’h, Frank
Nalli, Marianna
Silvestri, Romano
Brancale, Andrea
Coluccia, Antonio
Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics
title Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics
title_full Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics
title_fullStr Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics
title_full_unstemmed Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics
title_short Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics
title_sort modeling epac1 interactions with the allosteric inhibitor am-001 by co-solvent molecular dynamics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533256/
https://www.ncbi.nlm.nih.gov/pubmed/32700175
http://dx.doi.org/10.1007/s10822-020-00332-y
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