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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

AuthorsRoca, Carlos; Martínez-González, Loreto CSIC ORCID ; Daniel-Mozo, M.; Sastre, J. CSIC; Infantes, L. CSIC ORCID; Mansilla, A.; Chaves-Sanjuan, A.; Gonzalez-Rubio, Juana M; Gil, C; Cañada, F. Javier CSIC ORCID ; Martinez, A.; Sánchez-Barrena, María José CSIC ORCID; Campillo, Nuria E. CSIC ORCID
Issue Date2018
CitationJournal of Medicinal Chemistry 61: 5910- 5921 (2018)
AbstractProtein-protein interactions (PPIs) 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). Recently, the phenothiazine FD44 has been identified as an inhibitor of this PPI, decreasing the abnormally high synapse number and enhancing associative learning in a FXS animal model. Here, we have integrated advanced experimental and computational studies to obtain important structural insights into Drosophila 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 human NCS-1/Ric8a complex with improved binding potency. The crystal structure of the Drosophila NCS-1/IGS-1.76 complex demonstrates that the new inhibitor, although chemically different from FD44, shares the same mechanism of action and constitutes a new hit candidate for FXS.
Identifiersdoi: 10.1021/acs.jmedchem.8b00088
issn: 1520-4804
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