2. Academic Validation
  3. Discovery and characterization of a novel glucose-6-phosphate dehydrogenase (G6PD) inhibitor via high-throughput screening

Discovery and characterization of a novel glucose-6-phosphate dehydrogenase (G6PD) inhibitor via high-throughput screening

  • Bioorg Med Chem Lett. 2021 May 15:40:127905. doi: 10.1016/j.bmcl.2021.127905.
Zhongyuan Luo 1,  Daohai Du 1,  Yanjun Liu 2,  Tian Lu 2,  Liping Liu 2,  Hualiang Jiang 2,  Kaixian Chen 2,  Changliang Shan 3,  Cheng Luo 4
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia, Nanjing 210023, Jiangsu, China; The Center for Chemical Biology, 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.
  • 2 The Center for Chemical Biology, 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.
  • 3 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300350, China. Electronic address: changliangshan@nankai.edu.cn.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Qixia, Nanjing 210023, Jiangsu, China; The Center for Chemical Biology, 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 Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: cluo@simm.ac.cn.
PMID: 33689874 DOI: 10.1016/j.bmcl.2021.127905
Abstract

Altered glucose-6-phosphate dehydrogenase (G6PD) status is influential in many cellular pathophysiological processes and diseases, making G6PD a potential target for Cancer therapy. However, the available G6PD inhibitors are very limited and restricted. Here we developed a reducing equivalent nicotinamide adenine dinucleotide phosphate (NADPH) absorption photometry assay based on Enzyme kinetics to characterize G6PD activity. In this way, we performed a high-throughput screening (HTS) to an in house library. And then we identified compound named Wedelolactone inhibiting G6PD strongly in a non-competitive, reversible way. In addition, we did the surface Plasmon Resonance (SPR) assay and indicated the KD between Wedelolactone and G6PD protein was 3.64 μM. Furthermore, our basic colony formation assay showed the inhibitory effect of Wedelolactone on the proliferation of ovarian Cancer cells (IC50 ~ 10 µM). Thus, we provided a high-throughput screening assay to quickly and efficiently discover G6PD inhibitors, and identified Wedelolactone as a G6PD inhibitor, implying that Wedelolactone suppresses ovarian Cancer partly through targeting G6PD.

Keywords

Absorption photometry assay; Enzyme kinetics assay; Glucose-6-phosphate dehydrogenase inhibitor; High-throughput screening.

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