2. Academic Validation
  3. Discovery of PHGDH inhibitors by virtual screening and preliminary structure-activity relationship study

Discovery of PHGDH inhibitors by virtual screening and preliminary structure-activity relationship study

  • Bioorg Chem. 2022 Apr;121:105705. doi: 10.1016/j.bioorg.2022.105705.
Fu-Mao Zhang 1,  Liang Yuan 2,  Xin-Wei Shi 1,  Kai-Rui Feng 3,  Xiaojing Lan 4,  Cheng Huang 1,  Guo-Qiang Lin 1,  Ping Tian 1,  Min Huang 5,  Shuai Tang 6,  Dingding Gao 7
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine and School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 School of Pharmacy, Nanchang University, Nanchang 330006, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Pharmacy, Weifang Medical University, Weifang 261000, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 5 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: [email protected].
  • 7 Shanghai Frontiers Science Center for TCM Chemical Biology, Innovation Research Institute of Traditional Chinese Medicine and School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
PMID: 35235889 DOI: 10.1016/j.bioorg.2022.105705
Abstract

Phosphoglycerate dehydrogenase (PHGDH) is abnormally expressed in numerous malignant tumor cells and catalyzes the first step of serine biosynthesis, thus becoming a key drug target for antitumor treatment. In this study, compound B2 bearing a benzene-1,3-diamine scaffold was identified by structure-based virtual screening as a novel PHGDH inhibitor with moderate enzymatic activity. The structure-activity relationship study led to the discovery of compound C25 possessing improved enzymatic inhibitory activity and potent inhibitory activity on the proliferation of cells overexpressing PHGDH. The Enzyme kinetic assay confirmed that C25 inhibited PHGDH in a nicotinamide adenine dinucleotide (NAD+) competitive manner. Molecular docking and mutagenesis experiment on PHGDH collectively revealed the binding site and key interaction residues of C25 in the PHGDH catalytic site. Taken together, this study provides information on the structural diversity for a further development of potent PHGDH inhibitors.

Keywords

Antitumor; PHGDH; Structure-activity relationships; Virtual screening.

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