Issue 10, 2022

QSAR models reveal new EPAC-selective allosteric modulators


Exchange proteins directly activated by cAMP (EPAC) are guanine nucleotide exchange factors for the small GTPases, Rap1 and Rap2. They regulate several physiological functions and mitigation of their activity has been suggested as a possible treatment for multiple diseases such as cardiomyopathy, diabetes, chronic pain, and cancer. Several EPAC-specific modulators have been developed, however studies that quantify their structure–activity relationships are still lacking. Here we propose a quantitative structure–activity relationship (QSAR) model for a series of EPAC-specific compounds. The model demonstrated high reproducibility and predictivity and the predictive ability of the model was tested against a series of compounds that were unknown to the model. The compound with the highest predicted affinity was validated experimentally through fluorescence-based competition assays and NMR experiments revealed its mode of binding and mechanism of action as a partial agonist. The proposed QSAR model can, therefore, serve as an effective screening tool to identify promising EPAC-selective drug leads with enhanced potency.

Graphical abstract: QSAR models reveal new EPAC-selective allosteric modulators

Supplementary files

Article information

Article type
18 Apr 2022
02 Aug 2022
First published
03 Aug 2022
This article is Open Access
Creative Commons BY license

RSC Chem. Biol., 2022,3, 1230-1239

QSAR models reveal new EPAC-selective allosteric modulators

H. Mohamed, H. Shao, M. Akimoto, P. Darveau, M. R. MacKinnon, J. Magolan and G. Melacini, RSC Chem. Biol., 2022, 3, 1230 DOI: 10.1039/D2CB00106C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity