Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics
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Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics Marianna Bufano1 · Marion Laudette2,3 · Jean‑Paul Blondeau4 · Frank Lezoualc’h2,3 · Marianna Nalli1 · Romano Silvestri1 · Andrea Brancale5 · Antonio Coluccia1 Received: 25 February 2020 / Accepted: 13 July 2020 © The Author(s) 2020
Abstract 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. Keywords EPAC · Molecular Dynamics · Cosolvent Molecular Dynamics · Docking · PCA
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00332-y) contains supplementary material, which is available to authorized users. * Antonio Coluccia [email protected] 1
Department of Drug Chemistry and Technologies, Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
2
Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR‑1048, Cedex 04, 31432 Toulouse, France
3
Université de Toulouse - Paul Sabatier, Cedex 04, 31432 Toulouse, France
4
Faculté de Pharmacie, Université Paris-Sud, Châtenay‑Malabry Cedex, 92296 Paris, France
5
Cardiff School of Pharmacy and Pharmaceutical Sciences, King Edward VII Avenue, Cardiff CF103NB, UK
The cyclic adenosine monophosphate (cAMP) is a universal second messenger that regulates many biological processes, including cell proliferation, differentiation, and apoptosis [1]. The effects of cAMP in mammalian cells are mediated by at least three effector families: protein kinase A (PKA), exchange proteins activated by cAMP (EPAC) and ion channels bearing a cyclic nucleotide binding domains (CNBD). The EPAC proteins regulate a variety of physiologi
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