Discovery of novel glyceraldehyde-3-phosphate dehydrogenase inhibitor via docking-based virtual screening

Ting Li; Xiaoqin Tan; Ruirui Yang; Ying Miao; Min Zhang; Yun Xi; Rui Guo; Mingyue Zheng; Biao Li

doi:10.1016/j.bioorg.2020.103620

Discovery of novel glyceraldehyde-3-phosphate dehydrogenase inhibitor via docking-based virtual screening

Bioorg Chem. 2020 Mar:96:103620. doi: 10.1016/j.bioorg.2020.103620. Epub 2020 Jan 25.

Authors

Ting Li¹, Xiaoqin Tan², Ruirui Yang³, Ying Miao¹, Min Zhang¹, Yun Xi¹, Rui Guo¹, Mingyue Zheng⁴, Biao Li⁵

Affiliations

¹ Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai 200025, China.
² Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
³ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China; School of Life Science and Technology, ShanghaiTech University, 393 Huaxiazhong Road, Shanghai 200031, China.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China. Electronic address: myzheng@simm.ac.cn.
⁵ Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin Second Road, Shanghai 200025, China. Electronic address: lb10363@rjh.com.cn.

PMID: 32028064
DOI: 10.1016/j.bioorg.2020.103620

Abstract

Glycolysis is enhanced in cancer cells. Cancer cells utilize glycolysis as their primary energy source, even under aerobic conditions. This is known as the Warburg effect. Thus, effective inhibition of the glycolytic pathway is a crucial component of cancer therapy. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an important enzyme in glycolysis and overexpresses in cancers. Therefore, targeting GAPDH to inhibit its role in glycolysis is important for GAPDH functional studies and the treatment of cancers. However, only a few GAPDH inhibitors have been reported. In our current study, we identified a GAPDH inhibitor, DC-5163, using docking-based virtual screening and biochemical and biophysical analysis. DC-5163 is a small molecule compound that inhibits GAPDH enzyme activity and cancer cell proliferation (normal cells were tolerant to it). It can inhibit glycolysis pathway partially, which was manifested by decreased glucose uptake and lactic acid production. And it also leaded to cell death through apoptotic pathways. This study reflects the pivotal role of GAPDH in cancer cells and demonstrates that DC-5163 is a useful inhibitor and can be of value in studying the role of GAPDH and the development of new clinical cancer treatments.

Keywords: Cancer; Glyceraldehyde-3-phosphate dehydrogenase; Glycolysis; Inhibitor; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Drug Discovery
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Glyceraldehyde-3-Phosphate Dehydrogenases / antagonists & inhibitors*
Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism
Glycolysis / drug effects
Humans
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / enzymology
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology

Substances

Antineoplastic Agents
Enzyme Inhibitors
Small Molecule Libraries
Glyceraldehyde-3-Phosphate Dehydrogenases