Glucosylpolyphenols as Inhibitors of Aβ-Induced Fyn Kinase Activation and Tau Phosphorylation: Synthesis, Membrane Permeability, and Exploratory Target Assessment within the Scope of Type 2 Diabetes and Alzheimer’s Disease

Abstract

Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetesinduced dementia, there are no disease-modifying therapies able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aβ-induced Fyn kinase activation, while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aβ-induced Fyn kinase activation and decrease pTau levels at 10 μM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and -glucosidase. Both compounds are non-toxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.

Optimization of an in silico protocol to characterize membrane PAINS

“…13 In recent years, there has been a large interest in developing computational methods to identify membrane PAINS and characterize their mode of action. 9,16,17 The developed methodologies focused on quantifying the membrane deformations due to the presence of embedded potential membrane PAINS. Ingólfsson and co-workers 9 explored the membrane perturbation effects of several phytochemicals in membranes and mechanosensitive membrane proteins through a combination of gramicidin-based assays (experimental) and coarsegrained Molecular Dynamics (MD) simulations.…”

“…The developed protocol, which relied on computationally demanding umbrella sampling (US) simulations, worked as the basis for several subsequent methodologies. [16][17][18] The new implementations of the US protocol increased the molecular detail by using atomistic MD and significantly improved the description of the membrane energy barriers. 9,16,17 However, such methodologies are very computationally intensive, leading to limitations in their implementation, such as the use of single replicates and short MD simulations.…”

“…[16][17][18] The new implementations of the US protocol increased the molecular detail by using atomistic MD and significantly improved the description of the membrane energy barriers. 9,16,17 However, such methodologies are very computationally intensive, leading to limitations in their implementation, such as the use of single replicates and short MD simulations. 16,17 In this work, we have implemented a new optimized computational protocol for the identification and characterization of membrane PAINS.…”

1st Spring Virtual Meeting on Medicinal Chemistry

“…With a much more straightforward and efficient synthesis compared to other drug-like molecular entities with similar bioactivity in this therapeutic context, the most promising compounds, 1-[2,4,6-trihydroxy-3-(2,3,4,6-tetra-Omethyl-β-D-glucopyranosyl)phenyl]ethan-1-one and 4-(β-D-glucopyranosyl) benzene-1,2diyl dibenzoate were not cytotoxic towards neuronal cells in concentrations of up to 100 µM and 50 µM, respectively, while displaying favourable physicochemical characteristics that make them good candidates for further studies. In this communication, the synthesis and biological activity of these molecules will be explored in detail, and the potential for glucosylpolyphenols to be used as therapeutic agents against Alzheimer's Disease will be discussed [10].…”

Optimization of an in Silico Protocol Using Probe Permeabilities to Identify Membrane Pan-Assay Interference Compounds

“…Ingólfsson and co-workers explored the membrane perturbation effects of several phytochemicals in membranes and mechanosensitive membrane proteins through a combination of gramicidin-based assays (experimental) and coarse-grained molecular dynamics (MD) simulations. The developed protocol, which relied on computationally demanding umbrella sampling (US) simulations, worked as the basis for several subsequent methodologies. − …”