Conformational studies of glucose transporter 1 (GLUT1) as an anticancer drug target

Research output: Contribution to journalArticle

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Abstract

Glucose transporter 1 (GLUT1) is a facilitative glucose transporter overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. GLUT1 works through conformational switching from an outward-open (OOP) to an inward-open (IOP) conformation passing through an occluded conformation. It is critical to determine which conformation is preferred by bound ligands because the success of structure-based drug design depends on the appropriate starting conformation of the target protein. To find out the most favorable GLUT 1 conformation for ligand binding, we ran systemic molecular docking studies for different conformations of GLUT1 using known GLUT1 inhibitors. Our data revealed that the IOP is the preferred conformation and that residues Phe291, Phe379, Glu380, Trp388, and Trp412 may play critical roles in ligand binding to GLUT1. Our data suggests that conformational differences in these five amino acids in the different conformers of GLUT1 may be used to design ligands that inhibit GLUT1.

Original languageEnglish (US)
Article number2159
JournalMolecules
Volume24
Issue number11
DOIs
StatePublished - Jun 7 2019

Fingerprint

transporter
Facilitative Glucose Transport Proteins
glucose
drugs
Conformations
Pharmaceutical Preparations
Ligands
ligands
Protein Conformation
Drug Design
inhibitors
amino acids
Tumors
therapy
Neoplasms
tumors
cancer
proteins
Amino Acids

Keywords

  • Anticancer
  • Conformation
  • Docking
  • Drug design
  • Glucose transporter 1 (GLUT1)

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

Conformational studies of glucose transporter 1 (GLUT1) as an anticancer drug target. / Almahmoud, Suliman; Wang, Xiaofang; Vennerstrom, Jonathan L; Zhong, Haizhen Andrew.

In: Molecules, Vol. 24, No. 11, 2159, 07.06.2019.

Research output: Contribution to journalArticle

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N2 - Glucose transporter 1 (GLUT1) is a facilitative glucose transporter overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. GLUT1 works through conformational switching from an outward-open (OOP) to an inward-open (IOP) conformation passing through an occluded conformation. It is critical to determine which conformation is preferred by bound ligands because the success of structure-based drug design depends on the appropriate starting conformation of the target protein. To find out the most favorable GLUT 1 conformation for ligand binding, we ran systemic molecular docking studies for different conformations of GLUT1 using known GLUT1 inhibitors. Our data revealed that the IOP is the preferred conformation and that residues Phe291, Phe379, Glu380, Trp388, and Trp412 may play critical roles in ligand binding to GLUT1. Our data suggests that conformational differences in these five amino acids in the different conformers of GLUT1 may be used to design ligands that inhibit GLUT1.

AB - Glucose transporter 1 (GLUT1) is a facilitative glucose transporter overexpressed in various types of tumors; thus, it has been considered as an important target for cancer therapy. GLUT1 works through conformational switching from an outward-open (OOP) to an inward-open (IOP) conformation passing through an occluded conformation. It is critical to determine which conformation is preferred by bound ligands because the success of structure-based drug design depends on the appropriate starting conformation of the target protein. To find out the most favorable GLUT 1 conformation for ligand binding, we ran systemic molecular docking studies for different conformations of GLUT1 using known GLUT1 inhibitors. Our data revealed that the IOP is the preferred conformation and that residues Phe291, Phe379, Glu380, Trp388, and Trp412 may play critical roles in ligand binding to GLUT1. Our data suggests that conformational differences in these five amino acids in the different conformers of GLUT1 may be used to design ligands that inhibit GLUT1.

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