bims-glecem 2023-07-30 papers

Issue of 2023–07–30
six papers selected by
Dipsikha Biswas, Københavns Universitet

J Biomol Struct Dyn. 2023 Jul 27. 1-16

Discovery of novel and highly potential inhibitors of glycogen synthase kinase 3-beta (GSK-3β) through structure-based pharmacophore modeling, virtual computational screening, docking and in silico ADMET analysis.

Soumia Benghanem, Fouzia Mesli, Hadjadj Aoul Fatima Zohra, Chaida Nacereddine, Chenaffa Hadjer, Merzoug Abdellatif.

The protein Glycogen Synthase Kinase 3-Beta (GSK-3β), is a promising therapeutic target for treating various diseases such as neurodegenerative disorders, diabetes, inflammation and cancer. This study aims to investigate the potential of compounds targeting inflammation or carbohydrate metabolism to selectively inhibit GSK3β by binding to its ATP site. To achieve this goal, we filtered a database of 49367 molecules involved in carbohydrate metabolism or targeting inflammation using various computational analyses, including pharmacophore modeling, molecular docking, dynamic simulation, prime MM-GBSA calculation, and in silico ADME studies. We generated a pharmacophore model (hypo S: AADDHRR) using two different crystallographic complexes of GSK3β and evaluated the model's performance in identifying hits using various parameters, including EF, GH, ROC, AUC and BEDROC. Subsequently, we performed various dockings (HTVS, SP, XP and IFD) for the retrieved hits and found that, 5 out of the top 10 ranked compounds had the scaffold of pyrazolidine 3,5-dione, which has never been reported to inhibit kinases. We also conducted ADMET studies to and concluded that compound N6 exhibited the best pharmacokinetic profile passing the blood-brain barrier, possessing high lipophilicity and a high coefficient of skin permeability in the intestines, along with good bioavailability and low toxicity risk assessment. Dynamic simulation were also performed indicating that compounds N6 derived from pyrazolidine 3,5-dione demonstrated better binding potential for GSK3β during the simulation period. Therefore, we propose that compounds derived from pyrazolidine-3,5-dione, which modulate the activity of lysosomal alpha-glucosidase could serve as a novel scaffold for the selective inhibition of GSK-3β.Communicated by Ramaswamy H. Sarma.

Keywords: ADMET; ATP binding pocket; GSK-3β; Pharmacophore modeling; docking; dynamic simulations; pyrazolidine 3,5-dione

DOI: https://doi.org/10.1080/07391102.2023.2238062

Life (Basel). 2023 Jul 08. pii: 1529. [Epub ahead of print]13(7):

Glycogen Metabolism and Its Role in Growth and Encystation in Entamoeba histolytica.

Jordan Wesel, Cheryl Ingram-Smith.

Entamoeba histolytica is a parasitic protozoan that causes diarrheal disease in approximately 100 million people worldwide every year. E. histolytica has two forms, the growing trophozoite and the infectious cyst. Trophozoites colonizing the large intestine form cysts that are released into the environment. The ingestion of the cysts in contaminated food and water continues the disease cycle. Here, we investigated the role of glycogen in trophozoite growth and encystation. Glycogen is thought to provide precursors for the synthesis of chitin, a major component of the protective cyst wall. We propose that glycogen also serves as an energy source during metabolic adaptation to different nutrient environments. We examined the role of glycogen in E. histolytica by analyzing the growth and encystation of RNAi strains with reduced expression of the single gene-encoding glycogen synthase (GYS) or two of three genes encoding glycogen phosphorylase (PYG). The GYS RNAi strain had a greatly reduced glycogen accumulation, and both the GYS and PYG RNAi strains exhibited reduced growth in the glucose-poor medium. Both RNAi strains also showed reduced cyst production. Our results suggest glycogen synthesis and degradation are vital to the growth and adaptation of E. histolytica to a low-glucose environment such as that encountered in the large intestine.

Keywords: Entamoeba; encystation; glycogen; glycogen phosphorylase; glycogen synthase

DOI: https://doi.org/10.3390/life13071529

Int J Mol Sci. 2023 Jul 19. pii: 11638. [Epub ahead of print]24(14):

GSK3β Inhibition Ameliorates Atherosclerotic Calcification.

Xinjiang Cai, Yan Zhao, Yang Yang, Xiuju Wu, Li Zhang, Jocelyn A Ma, Jaden Ji, Kristina I Boström, Yucheng Yao.

Endothelial-mesenchymal transition (EndMT) drives endothelium to contribute to atherosclerotic calcification. In a previous study, we showed that glycogen synthase kinase-3β (GSK3β) inhibition induced β-catenin and reduced mothers against DPP homolog 1 (SMAD1) in order to redirect osteoblast-like cells towards endothelial lineage, thereby reducing vascular calcification in Matrix Gla Protein (Mgp) deficiency and diabetic Ins2Akita/wt mice. Here, we report that GSK3β inhibition or endothelial-specific deletion of GSK3β reduces atherosclerotic calcification. We also find that alterations in β-catenin and SMAD1 induced by GSK3β inhibition in the aortas of Apoe-/- mice are similar to Mgp-/- mice. Together, our results suggest that GSK3β inhibition reduces vascular calcification in atherosclerotic lesions through a similar mechanism to that in Mgp-/- mice.

Keywords: atherosclerosis; glycogen synthase kinase-3β; vascular calcification

DOI: https://doi.org/10.3390/ijms241411638

Eur J Med Res. 2023 Jul 24. 28(1): 253

French recommendations for the management of glycogen storage disease type III.

Camille Wicker, Aline Cano, Valérie Decostre, Roseline Froissart, François Maillot, Ariane Perry, François Petit, Catherine Voillot, Karim Wahbi, Joëlle Wenz, Pascal Laforêt, Philippe Labrune.

The aim of the Protocole National De Diagnostic et de Soins/French National Protocol for Diagnosis and Healthcare (PNDS) is to provide advice for health professionals on the optimum care provision and pathway for patients with glycogen storage disease type III (GSD III).The protocol aims at providing tools that make the diagnosis, defining the severity and different damages of the disease by detailing tests and explorations required for monitoring and diagnosis, better understanding the different aspects of the treatment, defining the modalities and organisation of the monitoring. This is a practical tool, to which health care professionals can refer. PNDS cannot, however, predict all specific cases, comorbidities, therapeutic particularities or hospital care protocols, and does not seek to serve as a substitute for the individual responsibility of the physician in front of his/her patient.

DOI: https://doi.org/10.1186/s40001-023-01212-5

Orphanet J Rare Dis. 2023 07 25. 18(1): 210

Data from the European registry for patients with McArdle disease (EUROMAC): functional status and social participation.

EUROMAC Consortium

BACKGROUND: The European registry for individuals with GSD5 and other muscle glycogenosis (EUROMAC) was launched to register rare muscle glycogenosis in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases. A network of twenty collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry.
METHODS: Following the initial report on demographics, neuromuscular features and comorbidity (2020), we here present the data on social participation, previous and current treatments (medication, supplements, diet and rehabilitation) and limitations. Furthermore, the following questionnaires were used: Fatigue severity scale (FSS), WHO Disability Assessment Scale (DAS 2.0), health related quality of life (SF36) and International Physical Activity Questionnaire (IPAQ).
RESULTS: Of 282 participants with confirmed diagnoses of muscle glycogenosis, 269 had GSD5. Of them 196 (73%) completed all questionnaires; for the others, the data were incomplete. The majority, 180 (67%) were currently working. Previous medical treatments included pain medication (23%) and rehabilitation treatment (60%). The carbohydrate-rich diet was reported to be beneficial for 68%, the low sucrose diet for 76% and the ketogenic diet for 88%. Almost all participants (93%) reported difficulties climbing stairs. The median FSS score was 5.22, indicating severe fatigue. The data from the WHODAS and IPAQ was not of sufficient quality to be interpreted.
CONCLUSIONS: The EUROMAC registry have provided insight into the functional and social status of participants with GSD5: most participants are socially active despite limitations in physical and daily life activities. Regular physical activity and different dietary approaches may alleviate fatigue and pain.

Keywords: Glycogen storage disease V; Health care; International registry; McArdle disease; Rare diseases

DOI: https://doi.org/10.1186/s13023-023-02825-z

Diabetes. 2023 Jul 28. pii: db230358. [Epub ahead of print]

AMPKγ3 controls muscle glucose uptake in recovery from exercise to recapture energy stores.

Kohei Kido, Nicolas O Eskesen, Nicolai S Henriksen, Johan Onslev, Jonas M Kristensen, Magnus R Larsen, Janne R Hingst, Jonas R Knudsen, Jesper B Birk, Nicoline R Andersen, Thomas E Jensen, Christian Pehmøller, Jørgen F P Wojtaszewski, Rasmus Kjøbsted.

Exercise increases muscle glucose uptake independently of insulin signaling and represents a cornerstone for the prevention of metabolic disorders. Pharmacological activation of the exerciseresponsive AMPK in skeletal muscle has been proven successful as a therapeutic approach to treat metabolic disorders by improving glucose homeostasis through the regulation of muscle glucose uptake. However, conflicting observations cloud the proposed role of AMPK as a necessary regulator of muscle glucose uptake during exercise. We show that glucose uptake increases in human skeletal muscle in the absence of AMPK activation during exercise and that exercisestimulated AMPKγ3 activity strongly correlates to muscle glucose uptake in the post-exercise period. In AMPKγ3-deficient mice, muscle glucose uptake is normally regulated during exercise and contractions but impaired in the recovery period from these stimuli. Impaired glucose uptake in recovery from exercise and contractions is associated to a lower glucose extraction, which can be explained by a diminished permeability to glucose and abundance of glucose transporter 4 (GLUT4) at the muscle plasma membrane. As a result, AMPKγ3-deficiency impairs muscle glycogen resynthesis following exercise. These results identify a physiological function of the AMPKγ3 complex in human and rodent skeletal muscle that serves to regulate glucose uptake in recovery from exercise to recapture muscle energy stores.

DOI: https://doi.org/10.2337/db23-0358