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A multidisciplinar study published in J. Med. Chem. by IQFR researchers has revealed key structural insights for the regulation of the NCS-1/Ric8a protein/protein interaction with small molecules. This has led to the discovery of a drug-like compound with promissing prospect for fragile X syndrome pharmacotherapy.

Protein-protein interactions (PPI) are known to play an essential role between the neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor Ric8a to regulate synapse function, emerging as a druggable interface for synaptopathies such as the Fragile X syndrome (FXS). In a previous study published in PNAS, the phenothiazine FD44 was identified as an inhibitor of this PPI, decreasing the abnormally high synapse number and enhancing associative learning in a FXS animal model. In this new work published in J. Med. Chem., we have integrated advanced experimental and computational studies to obtain important structural insights into NCS-1/FD44 recognition to understand the basis of its affinity and specificity and generate improved PPI regulators. This has allowed the identification of a new small drug-like molecule, IGS-1.76, which efficiently inhibits the NCS-1/Ric8a complex with improved binding potency. The crystal structure of the NCS-1/IGS-1.76 complex demonstrates that the new inhibitor, although chemically different to FD44, shares the same mechanism of action and constitutes a promissing candidate for FXS pharmacotherapy and related synaptopathies such as ADS, schizophrenia or Rett syndrome.

Reference:

Roca C, Martínez-González L, Daniel-Mozo M, Sastre J, Infantes L, Mansilla A, Chaves-Sanjuán A, González-Rubio JM, Gil C, Cañada J, Martínez A, *Sánchez-Barrena MJ and *Campillo NE (2018) Deciphering the inhibition of the neuronal calcium sensor 1 and the guanine exchange factor Ric8a with a small phenothiazine molecule for the rational generation of therapeutic synapse function regulators. Journal of Medicinal Chemistry. DOI: 10.1021/acs.jmedchem.8b00088.

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