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. Epub 2022 Feb 24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Enzyme Inhibitors* / chemistry
  • Molecular Docking Simulation
  • Phosphoglycerate Dehydrogenase*
  • Serine
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Serine
  • Phosphoglycerate Dehydrogenase