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

J Med Chem. 2018 Jul 26;61(14):5910-5921. doi: 10.1021/acs.jmedchem.8b00088. Epub 2018 Jul 17.

Abstract

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.

MeSH terms

  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Humans
  • Molecular Dynamics Simulation
  • Neuronal Calcium-Sensor Proteins / antagonists & inhibitors*
  • Neuronal Calcium-Sensor Proteins / chemistry
  • Neuronal Calcium-Sensor Proteins / metabolism
  • Neuropeptides / antagonists & inhibitors*
  • Neuropeptides / chemistry
  • Neuropeptides / metabolism
  • Phenothiazines / pharmacology*
  • Protein Conformation, alpha-Helical
  • Synapses / drug effects*
  • Synapses / physiology*

Substances

  • Guanine Nucleotide Exchange Factors
  • Neuronal Calcium-Sensor Proteins
  • Neuropeptides
  • Phenothiazines
  • Ric8A protein, human
  • frequenin calcium sensor proteins
  • phenothiazine