Ligand-based design of GLUT inhibitors as potential antitumor agents

Suliman Almahmoud; Wei Jin; Liying Geng; Jing Wang; Xiaofang Wang; Jonathan L. Vennerstrom; Haizhen A. Zhong

doi:10.1016/j.bmc.2020.115395

Ligand-based design of GLUT inhibitors as potential antitumor agents

Suliman Almahmoud, Wei Jin, Liying Geng, Jing Wang, Xiaofang Wang, Jonathan L. Vennerstrom, Haizhen A. Zhong

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities. From these, we identified that compounds 2, 5, 6 and 13 inhibited the cell viability in a dose-dependent manner and that the IC₅₀s of 2 and 6 are<10 µM concentration in the HCT116 colon cancer cell line. Lead compound 13 (NSC295720) was a GLUT1 inhibitor. Docking studies show that GLUT1 residues Phe291, Phe379, Glu380, Trp388, and Trp412 were important for inhibitor binding.

Original language	English (US)
Article number	115395
Journal	Bioorganic and Medicinal Chemistry
Volume	28
Issue number	7
DOIs	https://doi.org/10.1016/j.bmc.2020.115395
State	Published - Apr 1 2020

Keywords

Anticancer
Docking
GLUT1
Glucose
Pharmacophore

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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title = "Ligand-based design of GLUT inhibitors as potential antitumor agents",

abstract = "Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities. From these, we identified that compounds 2, 5, 6 and 13 inhibited the cell viability in a dose-dependent manner and that the IC50s of 2 and 6 are<10 µM concentration in the HCT116 colon cancer cell line. Lead compound 13 (NSC295720) was a GLUT1 inhibitor. Docking studies show that GLUT1 residues Phe291, Phe379, Glu380, Trp388, and Trp412 were important for inhibitor binding.",

keywords = "Anticancer, Docking, GLUT1, Glucose, Pharmacophore",

author = "Suliman Almahmoud and Wei Jin and Liying Geng and Jing Wang and Xiaofang Wang and Vennerstrom, {Jonathan L.} and Zhong, {Haizhen A.}",

note = "Funding Information: Suliman Almahmoud acknowledges The Saudi Arabian Cultural Mission (SACM) for financial support. This work was financially supported by the University of Nebraska at Omaha and NCI R01CA215389 to JW. Suliman Almahmoud was supported by the Ministry of Education Scholarship, Qassim University (Buraydah, Saudi Arabia). ",

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AU - Almahmoud, Suliman

AU - Jin, Wei

AU - Geng, Liying

AU - Wang, Jing

AU - Wang, Xiaofang

AU - Vennerstrom, Jonathan L.

AU - Zhong, Haizhen A.

N1 - Funding Information: Suliman Almahmoud acknowledges The Saudi Arabian Cultural Mission (SACM) for financial support. This work was financially supported by the University of Nebraska at Omaha and NCI R01CA215389 to JW. Suliman Almahmoud was supported by the Ministry of Education Scholarship, Qassim University (Buraydah, Saudi Arabia).

PY - 2020/4/1

Y1 - 2020/4/1

N2 - Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities. From these, we identified that compounds 2, 5, 6 and 13 inhibited the cell viability in a dose-dependent manner and that the IC50s of 2 and 6 are<10 µM concentration in the HCT116 colon cancer cell line. Lead compound 13 (NSC295720) was a GLUT1 inhibitor. Docking studies show that GLUT1 residues Phe291, Phe379, Glu380, Trp388, and Trp412 were important for inhibitor binding.

AB - Glucose transporters (GLUTs) regulate glucose uptake and are often overexpressed in several human tumors. To identify new chemotypes targeting GLUT1, we built a pharmacophore model and searched against a NCI compound database. Sixteen hit molecules with good docking scores were screened for GLUT1 inhibition and antiproliferative activities. From these, we identified that compounds 2, 5, 6 and 13 inhibited the cell viability in a dose-dependent manner and that the IC50s of 2 and 6 are<10 µM concentration in the HCT116 colon cancer cell line. Lead compound 13 (NSC295720) was a GLUT1 inhibitor. Docking studies show that GLUT1 residues Phe291, Phe379, Glu380, Trp388, and Trp412 were important for inhibitor binding.

KW - Anticancer

KW - Docking

KW - GLUT1

KW - Glucose

KW - Pharmacophore

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Ligand-based design of GLUT inhibitors as potential antitumor agents

Abstract

Keywords

ASJC Scopus subject areas

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