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 ORCID: https://orcid.org/0000-0002-9728-3419 and Coluccia, Antonio 2020. Modeling Epac1 interactions with the allosteric inhibitor AM-001 by co-solvent molecular dynamics. Journal of Computer-Aided Molecular Design 34 , pp. 1171-1179. 10.1007/s10822-020-00332-y

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy
Publisher:	Springer Verlag (Germany)
ISSN:	0920-654X
Date of First Compliant Deposit:	30 July 2020
Date of Acceptance:	9 July 2020
Last Modified:	05 Jan 2024 05:49
URI:	https://orca.cardiff.ac.uk/id/eprint/133881

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