Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase

The pathogenesis of several neurodegenerative diseases such as Alzheimer’s or Huntington’s disease has been associated with metabolic dysfunctions caused by imbalances in the brain and cerebral spinal fluid levels of neuroactive metabolites. Kynurenine monooxygenase (KMO) is considered an ideal therapeutic target for the regulation of neuroactive tryptophan metabolites. Despite significant efforts, the known KMO inhibitors lack blood–brain barrier (BBB) permeability and upon the mimicking of the substrate binding mode, are subject to produce reactive oxygen species as a side reaction. The computational drug design is further complicated by the absence of complete crystal structure information for human KMO (hKMO). In the current work, we performed virtual screening of readily available compounds using several protein–ligand complex pharmacophores. Each of the pharmacophores accounts for one of three distinct reported KMO protein-inhibitor binding conformations. As a result, six novel KMO inhibitors were discovered based on an in vitro fluorescence assay. Compounds VS1 and VS6 were predicted to be BBB permeable and avoid the hydrogen peroxide production dilemma, making them valuable, novel hit compounds for further drug property optimization and advancement in the drug design pipeline.     

Porphyrin acidity and metal ion coordination revisited: electronic substitution effects

Macrocycle acidity and Zn²⁺ ion coordination are reported for three porphyrin derivatives which differ in both steric and electronic substitution effects on the macrocycle π-conjugated system. The role of the electronic substitution effects in the macrocycle deprotonation and metal ion chelating was found to be dominating whereas the macrocycle nonplanar distortions contribute to the acidity and metal chelation rate of the studied porphyrins in less extent. The contributions of both resonance and inductive electronic substitution effects have been distinguished based on the relationship between the weighted sum of resonance and inductive Hammett constants and the acidity and metal ion chelation rate.     

Smoothness spaces of higher order on lower dimensional subsets of the Euclidean space

We study Sobolev type spaces defined in terms of sharp maximal functions on Ahlfors regular subsets of and the relation between these spaces and traces of classical Sobolev spaces.     

Measure Density and Extension of Besov and Triebel–Lizorkin Functions

We show that a domain is an extension domain for a Haj?asz–Besov or for a Haj?asz–Triebel–Lizorkin space if and only if it satisfies a measure density condition. We use a modification of the Whitney extension where integral averages are replaced by median values, which allows us to handle also the case \(0<p<1\). The necessity of the measure density condition is derived from embedding theorems; in the case of Haj?asz–Besov spaces we apply an optimal Lorentz-type Sobolev embedding theorem which we prove using a new interpolation result. This interpolation theorem says that Haj?asz–Besov spaces are intermediate spaces between \(L^p\) and Haj?asz–Sobolev spaces. Our results are proved in the setting of a metric measure space, but most of them are new even in the Euclidean setting, for instance, we obtain a characterization of extension domains for classical Besov spaces \(B^s_{p,q}\), \(0<s<1\), \(0<p<\infty \), \(0<q\le \infty \), defined via the \(L^p\)-modulus of smoothness of a function.     

Muckenhoupt Ap-properties of Distance Functions and Applications to Hardy–Sobolev -type Inequalities

Potential Analysis - Let X be a metric space equipped with a doubling measure. We consider weights w(x) = dist(x,E)?α, where E is a closed set in X and $\alpha \in \mathbb {R}$ . We...     

Platycodin D,a natural component of Platycodon grandiflorum,prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection by hindering membrane fusion

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to global public health. Herbal medicines and their derived natural products have drawn much attention in the treatment of COVID-19, but the detailed mechanisms by which natural products inhibit SARS-CoV-2 have not been elucidated. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection routes via lysosome- and transmembrane protease serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by the pharmacological inhibition or gene silencing of NPC1, which is mutated in patients with Niemann–Pick type C (NPC) displaying disrupted membrane cholesterol distribution. Finally, readily available local foods or herbal medicines containing PG root show similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that briefly disrupting the distribution of membrane cholesterol is a potential novel therapeutic strategy for SARS-CoV-2 infection.Subject terms: Viral infection, Lipid signalling