Recent studies suggested that activation of Uncoupling Protein 1 (UCP1) has become an appealing therapeutic strategy against obesity and diabetes. In our research, the 3D structure of UCP1 was constructed through homology modelling, refined through molecular dynamics simulation, and evaluated by Ramachandran plot, the molecular docking of UCP1 activators brought about the proposal of an interaction mode inside the UCP1 active site. Remarkably, Reside Lys126 formed hydrogen bond; residues Pro121, Val125, Tyr146, Tyr149 and Arg150 formed hydrophobic interaction, which are key amino acids within UCP1 site. Then a pharmacophore model was generated consisting of three hydrophobic groups, a negative center and an additional hydrophobic group. Pharmacophore-based virutal screening of Specs database yield 5 hits. In vitro assay indicated ZINC 04660290 significantly increased the protein expression of UCP1 and decreased the fat droplet in a dose-dependent manner. Besides, pharmacokinetic properties were predicted for those five compounds through ADME/T prediction. All of these will guide us to design new UCP1 activators for the treatment of obesity and diabetes.
Download full-text PDF |
Source |
---|---|
http://dx.doi.org/10.1002/minf.201900030 | DOI Listing |
Commun Biol
January 2025
State Key Laboratory of Swine and Poultry Breeding Industry, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, Sichuan, P. R. China.
Uncoupling protein 1 (UCP1) is a crucial protein located in the mitochondrial inner membrane that mediates nonshivering thermogenesis. However, the molecular mechanisms by which enhancer-promoter chromatin interactions control Ucp1 transcriptional regulation in brown adipose tissue (BAT) are unclear. Here, we employed circularized chromosome conformation capture coupled with next-generation sequencing (4C-seq) to generate high-resolution chromatin interaction profiles of Ucp1 in interscapular brown adipose tissue (iBAT) and epididymal white adipose tissue (eWAT) and revealed marked changes in Ucp1 chromatin interaction between iBAT and eWAT.
View Article and Find Full Text PDFDiabetes
January 2025
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
To curb the obesity epidemic, it is imperative that we improve our understanding of the mechanisms controlling fat mass and body weight regulation. While great progress has been made in mapping the biological feedback forces opposing weight loss, the mechanisms countering weight gain remain less well defined. Here, we integrate a mouse model of intragastric overfeeding with a comprehensive evaluation of the regulatory aspects of energy balance, encompassing food intake, energy expenditure, and fecal energy excretion.
View Article and Find Full Text PDFArch Physiol Biochem
January 2025
Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, Norway.
Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) plays a crucial role in regulation of metabolic homeostasis. To understand the role of the catalytic α2 subunit of AMPK in skeletal muscle energy metabolism, myotube cultures were established from and mice. Myotubes from mice had lower basal oleic acid and glucose oxidation compared to myotubes from mice.
View Article and Find Full Text PDFBlood Adv
January 2025
KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.
Allosteric regulation of ADAMTS13 (A Disintegrin And Metalloproteinase with ThromboSpondin type-1 motif, member 13) activity involves an interaction between its Spacer (S) and CUB1-2 domains to keep the enzyme in a closed, latent conformation. Monoclonal antibodies (mAb) uncouple the S-CUB interaction to open the ADAMTS13 conformation and thereby disrupt the global enzyme latency. The molecular mechanism behind this mAb-induced allostery remains poorly understood.
View Article and Find Full Text PDFGenes (Basel)
November 2024
The New Zealand Institute for Plant and Food Research Limited, Private Bag 11600, Palmerston North 4442, New Zealand.
Background: Larvae development is a critical step in aquaculture, yet the development of immune and stress responses during this early phase of life is not well understood. Snapper is a species that has been selected as a candidate for aquaculture in New Zealand.
Methods: In this study we explore a set of 18 genes identified as potentially being involved in the stress and immune responses of snapper larvae during the first 30 days of development.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!