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Conditioned suppression is a useful paradigm for measuring learned avoidance. In most conditioned suppression studies, forward conditioning is used where a cue predicts an aversive stimulus. However, backward conditioning, in which an aversive stimulus predicts a cue, provides unique insights into learned avoidance due to its influence on both conditioned excitation and inhibition.
View Article and Find Full Text PDFAPH Inhibitors that Reverse Aminoglycoside Resistance in Enterococcus casseliflavus.
ChemMedChem
January 2025
CBS: Centre de Biologie Structurale, ABCIS, 29 rue de Navacelles, 34090, Montpellier, FRANCE.
Aminoglycoside-phosphotransferases (APHs) are a class of bacterial enzymes that mediate acquired resistance to aminoglycoside antibiotics. Here we report the identification of small molecules counteracting aminoglycoside resistance in Enterococcus casseliflavus. Molecular dynamics simulations were performed to identify an allosteric pocket in three APH enzymes belonging to 3' and 2'' subfamilies in which we then screened, in silico, 12,000 small molecules.
View Article and Find Full Text PDFDeveloping Allosteric Chaperones for -Associated Disorders-An Integrated Computational and Experimental Approach.
Int J Mol Sci
December 2024
Gain Therapeutics Sucursal en España, Parc Científic de Barcelona, 08028 Barcelona, Spain.
Mutations in the gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), are associated with Gaucher disease and increased risk of Parkinson's disease. This study describes the discovery and characterization of novel allosteric pharmacological chaperones for GCase through an innovative computational approach combined with experimental validation. Utilizing virtual screening and structure-activity relationship optimization, researchers identified several compounds that significantly enhance GCase activity and stability across various cellular models, including patient-derived fibroblasts and neuronal cells harboring mutations.
View Article and Find Full Text PDFGanaxolone: A Review in Epileptic Seizures Associated with Cyclin-Dependent Kinase-Like 5 Deficiency Disorder.
Paediatr Drugs
January 2025
Springer Nature, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.
Oral ganaxolone (ZTALMY), a synthetic analogue of the endogenous neuroactive steroid allopregnanolone, acts as a positive allosteric modulator of synaptic and extra-synaptic γ-aminobutyric acid (GABA) type A receptor function in the CNS. In the EU and the UK, it is approved for the adjunctive treatment of epileptic seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2-17 years. In a multinational phase III study (Marigold), 17 weeks' therapy with adjunctive ganaxolone, administered orally three times daily with food, significantly reduced 28-day major motor seizure frequency from baseline versus placebo in patients aged 2-19 years with CDD-associated refractory epilepsy.
View Article and Find Full Text PDFCDK2 Allosteric Modulators: The New Route in the Design of New Drugs as Anticancer and Non-hormonal Contraceptives.
Curr Med Chem
January 2025
Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutcihe (STEBICEF) Università di Palermo, Via Archirafi 32, 90123 Palermo.
CDK2 plays a pivotal role in controlling the cell cycle progression in eukaryotes and for this reason, it has been the subject of several studies for suitable inhibitors in the last decades. But more than 30 years of basic research have not generated an inhibitor as marketed drugs. Some inhibitors are to date in early phase clinical development.
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