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
datasetposted on 02.07.2018, 00:00 by Carlos Roca, Loreto Martinez-González, Miguel Daniel-Mozo, Javier Sastre, Lourdes Infantes, Alicia Mansilla, Antonio Chaves-Sanjuan, Juana María González-Rubio, Carmen Gil, F. Javier Cañada, Ana Martinez, María José Sanchez-Barrena, Nuria E. Campillo
Protein–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.
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drug-like moleculesynapse numberRational Generationdruggable interfacephenothiazine FD 44Small Phenothiazine MoleculeIGScalcium sensor 1binding potencyPPI regulatorsFXS animal modelsynapse functionguanine exchange factor Ric 8aNeuronal Calcium Sensor 1inhibitorGuanine Exchange Factor Ric 8acrystal structureX syndromeDrosophilaNCS