Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods

The large neutral amino acid transporter 1 (LAT1) is a promising anticancer target that is required for the cellular uptake of essential amino acids that serve as building blocks for cancer growth and proliferation. Here, we report a structure-based approach to identify chemically diverse and potent inhibitors of LAT1. First, a homology model of LAT1 that is based on the atomic structures of the prokaryotic homologs was constructed. Molecular docking of nitrogen mustards (NMs) with a wide range of affinity allowed for deriving a common binding mode that could explain the structure−activity relationship pattern in NMs. Subsequently, validated binding hypotheses were subjected to molecular dynamics simulation, which allowed for extracting a set of dynamic pharmacophores. Finally, a library of ~1.1 million molecules was virtually screened against these pharmacophores, followed by docking. Biological testing of the 30 top-ranked hits revealed 13 actives, with the best compound showing an IC50 value in the sub-μM range.© 2018 by the author

Bam 1-90 Blue poison-arrow frog, BamHI, pUC18 library Dendrobates tinctorius genomic clone 1, genomic survey sequence

FI849606-FI84961

Bam 1-90 Blue poison-arrow frog, BamHI, pUC18 library Dendrobates tinctorius genomic clone 1, genomic survey sequence

FI849606-FI84961

p62 filaments capture and present ubiquitinated cargos for autophagy

The removal of misfolded, ubiquitinated proteins is an essential part of the protein quality control. The ubiquitin‐proteasome system (UPS) and autophagy are two interconnected pathways that mediate the degradation of such proteins. During autophagy, ubiquitinated proteins are clustered in a p62‐dependent manner and are subsequently engulfed by autophagosomes. However, the nature of the protein substrates targeted for autophagy is unclear. Here, we developed a reconstituted system using purified components and show that p62 and ubiquitinated proteins spontaneously coalesce into larger clusters. Efficient cluster formation requires substrates modified with at least two ubiquitin chains longer than three moieties and is based on p62 filaments cross‐linked by the substrates. The reaction is inhibited by free ubiquitin, K48‐, and K63‐linked ubiquitin chains, as well as by the autophagosomal marker LC3B, suggesting a tight cross talk with general proteostasis and autophagosome formation. Our study provides mechanistic insights on how substrates are channeled into autophagy.© 2018 The Author

Use of hypnotic drugs among children, adolescents and young adults in Scandinavia

The dataset contains information about use of hypnotics in the Scandinavian countries, Denmark, Norway and Sweden. The categories of hypnotics described are: N05CH01 - Melatonine, N05CF* - Z drugs and R06AD* - H1 receptor antagonists. The dataset consists of 2 files: drug_use.csv census.csv Drug and census data were derived from the following national resources in the public domain: Drug statistics data: https://sdb.socialstyrelsen.se/if_lak/val.aspx (download date: 2020.06.15) http://www.norpd.no/ (download date: 2020.12.06) http://www.medstat.dk/ (download date: 2020.11.26) Census data: http://www.statistikdatabasen.scb.se (download date: 2020.06.12) https://www.ssb.no/ (download date: 2020.06.15) https://statistikbanken.dk (download date: 2020.06.12) The source data owners take no responsibily for interpretation or analysis of data performed by third parties. Source data owners should be attributed when data are used. Consult data owners websites for details about attribution. File descriptions: drug_use.csv This file contains aggregated information about the total number of unique users and the total amount of drug daily doses, by the categorical variables atc, year, country, sex and age. The categorical variables have the following valuesets country (DK, NO, SE, SC), SC means Scandinavia and includes DK, SE and NO year (2012 - 2019) age (5-9, 10-14, 15-19, 20-24, 5-24) sex (M,F, MF), MF means Male and Female The variables prev_pr_1000 and ddd_pr_1000 are the results of dividing the variables n_users and ddd by the total population size (npop) in that country, year, agegroup and sex category. These census informations are also available in the census.csv file. Since ddd information is only available in Norway and Denmark, the ddd_pr_1000 for Scandinavia is based only on data from Denmark and Norway. The denominator for this calculation is in the variable called npop_excl_se. census.csv This file contains census data for each country grouped by sex and age in one year intervals. Use this file if you want to calculate population denominators for alternative aggregations of data in the drug_use.csv fil

Theoretical and Experimental Studies on Inclusion Complexes of Pinostrobin and β-Cyclodextrins

Pinostrobin (PNS) belongs to the flavanone subclass of flavonoids which shows several biological activities such as anti-inflammatory, anti-cancerogenic, anti-viral and anti-oxidative effects. Similar to other flavonoids, PNS has a quite low water solubility. The purpose of this work is to improve the solubility and the biological activities of PNS by forming inclusion complexes with β-cyclodextrin (βCD) and its derivatives, heptakis-(2,6-di-O-methyl)-β-cyclodextrin (2,6-DMβCD) and (2-hydroxypropyl)-β-cyclodextrin (HPβCD). The AL-type diagram of the phase solubility studies of PNS exhibited the formed inclusion complexes with the 1:1 molar ratio. Inclusion complexes were prepared by the freeze-drying method and were characterized by differential scanning calorimetry (DSC). Two-dimensional nuclear magnetic resonance (2D-NMR) and steered molecular dynamics (SMD) simulation revealed two different binding modes of PNS, i.e., its phenyl- (P-PNS) and chromone- (C-PNS) rings preferably inserted into the cavity of βCD derivatives whilst only one orientation of PNS, where the C-PNS ring is inside the cavity, was detected in the case of the parental βCD. All PNS/βCDs complexes had a higher dissolution rate than free PNS. Both PNS and its complexes significantly exerted a lowering effect on the IL-6 secretion in LPS-stimulated macrophages and showed a moderate cytotoxic effect against MCF-7 and HeLa cancer cell lines in vitro.© 2018 by the author