Virtual Screening-Accelerated Discovery of a Phosphodiesterase 9 Inhibitor with Neuroprotective Effects in the Kainate Toxicity In Vitro Model

Abstract

In the central nervous system, some specific phosphodiesterase (PDE) isoforms modulate pathways involved in neuronal plasticity. Accumulating evidence suggests that PDE9 may be a promising therapeutic target for neurodegenerative diseases. In the current study, computational techniques were used to identify a nature-inspired PDE9 inhibitor bearing the scaffold of an isoflavone, starting from a database of synthetic small molecules using a ligand-based approach. Furthermore, docking studies supported by molecular dynamics investigations allowed us to evaluate the features of the ligand−target complex. In vitro assays confirmed the computational results, showing that the selected compound inhibits the enzyme in the nanomolar range. Additionally, we evaluated the expression of gene and protein levels of PDE9 in organotypic hippocampal slices, observing an increase following exposure to kainate (KA). Importantly, the PDE9 inhibitor reduced CA3 damage induced by KA in a dose-dependent manner in organotypic hippocampal slices. Taken together, these observations strongly support the potential of the identified nature-inspired PDE9 inhibitor and suggest that such a molecule could represent a promising lead compound to develop novel therapeutic tools against neurological diseases..

In Silico Analysis of Selected Glycyrrhiza glabra (Licorice) Constituents: Exploring Their Modulatory Effects on Human Superoxide Dismutase, Human Phosphodiesterase-9 and Human Dipeptidyl Peptidase-4

“…In the current study, four ligands (glycyrrhizic acid, glabridin, liquiritigenin and isoliquiritin) of G. glabra (Licorice) have interacted with the Thr363 amino acid residue of hPDE 9 enzyme. Similarly in the present investigation, carbenoxolone has shown interaction with both His 252 and His 296 amino acid residue of the hPDE 9 enzyme, which was on par with the previous report [ 19 ].…”