期刊
BIOORGANIC CHEMISTRY
卷 121, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105705
关键词
Virtual screening; PHGDH; Structure-activity relationships; Antitumor
资金
- National Natural Science Foundation of China [81903423, 91957126]
- Shanghai Sailing Program [19YF1449300]
- Program of Shanghai Academic/Technology Research Leader [20XD1403600, 20XD1424800]
- Shanghai Municipal Education Commission [2019-01-07-00-10-E00072]
- Science and Technology Commission of Shanghai Municipality [20400750300]
- Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine [ZYYCXTD-D-202004]
In this study, a novel PHGDH inhibitor, compound C25, was identified with improved enzymatic inhibitory activity and potent inhibitory activity on the proliferation of cells overexpressing PHGDH. Enzyme kinetic assay confirmed that C25 inhibited PHGDH in a competitive manner with NAD(+). Molecular docking and mutagenesis experiments revealed the binding site and key interaction residues of C25 in the PHGDH catalytic site, providing structural diversity for the development of potent PHGDH inhibitors.
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.
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