GLUT3 inhibitor discovery through in silico ligand screening and in vivo validation in eukaryotic expression systems.

Binding Sites Biological Transport / drug effects Cell Line, Tumor Cell Survival / drug effects Drug Discovery Glucose Transporter Type 1 / antagonists & inhibitors Glucose Transporter Type 2 / antagonists & inhibitors Glucose Transporter Type 3 / antagonists & inhibitors Glucose Transporter Type 4 / antagonists & inhibitors Glucose Transporter Type 5 / antagonists & inhibitors Heterocyclic Compounds, 3-Ring / chemistry High-Throughput Screening Assays Humans Models, Molecular Neoplasms / drug therapy Protein Binding Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Interaction Domains and Motifs Saccharomyces cerevisiae / drug effects Saccharomyces cerevisiae Proteins / antagonists & inhibitors Small Molecule Libraries / chemistry

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
26 01 2022
Historique:
received: 13 10 2021
accepted: 06 01 2022
entrez: 27 1 2022
pubmed: 28 1 2022
medline: 5 3 2022
Statut: epublish

Résumé

The passive transport of glucose and related hexoses in human cells is facilitated by members of the glucose transporter family (GLUT, SLC2 gene family). GLUT3 is a high-affinity glucose transporter primarily responsible for glucose entry in neurons. Changes in its expression have been implicated in neurodegenerative diseases and cancer. GLUT3 inhibitors can provide new ways to probe the pathophysiological role of GLUT3 and tackle GLUT3-dependent cancers. Through in silico screening of an ~ 8 million compounds library against the inward- and outward-facing models of GLUT3, we selected ~ 200 ligand candidates. These were tested for in vivo inhibition of GLUT3 expressed in hexose transporter-deficient yeast cells, resulting in six new GLUT3 inhibitors. Examining their specificity for GLUT1-5 revealed that the most potent GLUT3 inhibitor (G3iA, IC

Identifiants

DOI: 10.1038/s41598-022-05383-9 PMID: 35082341 PMC: PMC8791944
pubmed: 35082341
doi: 10.1038/s41598-022-05383-9
pii: 10.1038/s41598-022-05383-9
pmc: PMC8791944
doi:

Substances chimiques

Glucose Transporter Type 1 0
Glucose Transporter Type 2 0
Glucose Transporter Type 3 0
Glucose Transporter Type 4 0
Glucose Transporter Type 5 0
Heterocyclic Compounds, 3-Ring 0
Saccharomyces cerevisiae Proteins 0
Small Molecule Libraries 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Validation Study

Langues

eng

Sous-ensembles de citation

IM

Pagination

1429

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM123103
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01-GM123103
Pays : United States

Informations de copyright

© 2022. The Author(s).

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Auteurs

Cristina V Iancu (CV)

East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, 27834, USA.

Giovanni Bocci (G)

Translational Informatics Division, Department of Internal Medicine, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA.

Mohd Ishtikhar (M)

East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, 27834, USA.

Moumita Khamrai (M)

East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, 27834, USA.

Mislav Oreb (M)

Institute of Molecular Biosciences, Faculty of Biological Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany.

Tudor I Oprea (TI)

Translational Informatics Division, Department of Internal Medicine, The University of New Mexico School of Medicine, Albuquerque, NM, 87131, USA. toprea@salud.unm.edu.
UNM Comprehensive Cancer Center, The University of New Mexico, Albuquerque, NM, 87131, USA. toprea@salud.unm.edu.
Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. toprea@salud.unm.edu.
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. toprea@salud.unm.edu.

Jun-Yong Choe (JY)

East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, 27834, USA. choej18@ecu.edu.
Department of Chemistry, East Carolina University, Greenville, NC, 27834, USA. choej18@ecu.edu.
Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA. choej18@ecu.edu.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Sites de fixation › GLUT3 inhibitor discovery through in silico...
questionsmedicales.fr › Métabolisme › Transport biologique › GLUT3 inhibitor discovery through in silico...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › GLUT3 inhibitor discovery through in silico...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Survie cellulaire › GLUT3 inhibitor discovery through in silico...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › GLUT3 inhibitor discovery through in silico...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs de glucose par diffusion facilitée › Transporteur de glucose de type 1 › GLUT3 inhibitor discovery through in silico...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs de glucose par diffusion facilitée › Transporteur de glucose de type 2 › GLUT3 inhibitor discovery through in silico...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de tissu nerveux › Transporteur de glucose de type 3 › GLUT3 inhibitor discovery through in silico...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Protéines transporteurs de solutés › Transporteurs de glucose par diffusion facilitée › Transporteur de glucose de type 4 › GLUT3 inhibitor discovery through in silico...
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