Biological evaluation and SAR analysis of novel covalent inhibitors against fructose-1,6-bisphosphatase.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: England NLM ID: 9413298 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1464-3391 (Electronic) Linking ISSN: 09680896 NLM ISO Abbreviation: Bioorg Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Elsevier Science
      Original Publication: Oxford : New York : Pergamon Press, c1993-
    • Subject Terms:
      Enzyme Inhibitors/*chemistry ; Fructose-Bisphosphatase/*antagonists & inhibitors ; Styrenes/*chemistry; Allosteric Site ; Amino Acid Sequence ; Animals ; Drug Design ; Enzyme Inhibitors/metabolism ; Gluconeogenesis ; Glucose/metabolism ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Humans ; Isomerism ; Kinetics ; Mice ; Molecular Docking Simulation ; Protein Binding ; Structure-Activity Relationship ; Styrenes/metabolism
    • Abstract:
      Fructose-1,6-bisphosphatase (FBPase) is an attractive target for affecting the GNG pathway. In our previous study, the C128 site of FBPase has been identified as a new allosteric site, where several nitrovinyl compounds can bind to inhibit FBPase activity. Herein, a series of nitrostyrene derivatives were further synthesized, and their inhibitory activities against FBPase were investigated in vitro. Most of the prepared nitrostyrene compounds exhibit potent FBPase inhibition (IC 50  < 10 μM). Specifically, when the substituents of F, Cl, OCH 3 , CF 3 , OH, COOH, or 2-nitrovinyl were installed at the R 2 (meta-) position of the benzene ring, the FBPase inhibitory activities of the resulting compounds increased 4.5-55 folds compared to those compounds with the same groups at the R 1 (para-) position. In addition, the preferred substituents at the R 3 position were Cl or Br, thus compound HS36 exhibited the most potent inhibitory activity (IC 50  = 0.15 μM). The molecular docking and site-directed mutation suggest that C128 and N125 are essential for the binding of HS36 and FBPase, which is consistent with the C128-N125-S123 allosteric inhibition mechanism. The reaction enthalpy calculations show that the order of the reactions of compounds with thiol groups at the R 3 position is Cl > H > CH 3 . CoMSIA analysis is consistent with our proposed binding mode. The effect of compounds HS12 and HS36 on glucose production in primary mouse hepatocytes were further evaluated, showing that the inhibition was 71% and 41% at 100 μM, respectively.
      Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2020 Elsevier Ltd. All rights reserved.)
    • Contributed Indexing:
      Keywords: Covalent inhibitors; FBPase inhibitors; Fructose-1,6-bisphosphatase (FBPase)
    • Accession Number:
      0 (Enzyme Inhibitors)
      0 (Styrenes)
      5287E3OUAV (beta-nitrostyrene)
      EC 3.1.3.11 (Fructose-Bisphosphatase)
      IY9XDZ35W2 (Glucose)
    • Publication Date:
      Date Created: 20200824 Date Completed: 20210615 Latest Revision: 20210615
    • Publication Date:
      20221213
    • Accession Number:
      10.1016/j.bmc.2020.115624
    • Accession Number:
      32828433