A Perspective on Natural and Nature-Inspired Small Molecules Targeting Phosphodiesterase 9 (PDE9): Chances and Challenges against Neurodegeneration

Abstract

As life expectancy increases, dementia affects a growing number of people worldwide. Besides current treatments, phosphodiesterase 9 (PDE9) represents an alternative target for developing innovative small molecules to contrast neurodegeneration. PDE inhibition promotes neurotransmitter release, amelioration of microvascular dysfunction, and neuronal plasticity. This review will provide an update on natural and nature-inspired PDE9 inhibitors, with a focus on the structural features of PDE9 that encourage the development of isoform-selective ligands. The expression in the brain, the presence within its structure of a peculiar accessory pocket, the asymmetry between the two subunits composing the protein dimer, and the selectivity towards chiral species make PDE9 a suitable target to develop specific inhibitors. Additionally, the world of natural compounds is an ideal source for identifying novel, possibly asymmetric, scaffolds, and xanthines, flavonoids, neolignans, and their derivatives are currently being studied. In this review, the available literature data were interpreted and clarified, from a structural point of view, taking advantage of molecular modeling: 3D structures of ligand-target complexes were retrieved, or built, and discussed.

One-Pot Surface Modification of β-Cu2O NPs for Biocatalytic Performance against A-549 Lung Carcinoma Cell Lines through Docking Analysis

“…Recently, transition-metal complexes containing l -ascorbic acid (LAA) and poly­(ethylene glycol) (PEG) derivatives have been reported and used in anticarcinoma activity . Cuprous oxide nanoparticles (β-Cu 2 O NPs) of the cuprite phase have gained special interest among transition-metal oxides because of their efficacy as nanofluids, sensors, antimicrobial applications, catalysts, superconductors, energy storage systems, and anticarcinoma agents. , Studies on the interaction of small molecules with proteins are important for the investigation, morphology, and designing of novel drugs effective against anticarcinoma activity . These β-Cu 2 O NPs can bind with proteins via three types of noncovalent interactions like electrostatic binding, metal groove binding, and intercalation binding modes .…”

Current Modulation of Guanylate Cyclase Pathway Activity—Mechanism and Clinical Implications

“…There are PDE5 located especially in cardiovascular system, PDE6 found in the retina and PDE9 present in heart muscle and brain. In this condition, modulation of PDE5 and PDE9 function is interesting as a cardiovascular therapeutic option [ 73 , 74 , 75 ].…”

“…These findings support future investigation into the therapeutic potential of CRD-733 in human heart failure [ 85 , 86 , 87 ]. Inhibition of brain PDE9 may improve synaptic plasticity, behavior; thus, PDE9 inhibitors have been advanced into initial clinical studies to assess the potential to improve cognitive function in patients with Alzheimer’s disease and schizophrenia [ 75 , 88 ].…”

Anti-Inflammatory Effects of Psoralen Derivatives on RAW264.7 Cells via Regulation of the NF-κB and MAPK Signaling Pathways

“…Therefore, interest in developing new drugs from natural products is once again growing; however, the way this phenomenon is developed currently differs significantly from the past. Recently, this method has been accelerating the “reuse” of nature-inspired compounds [ 14 , 15 ].…”