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Updated: Jun 7, 2025

Multi-target Parallel Processing Approach for Gene-to-structure Determination of the Influenza Polymerase PB2 Subunit
22:10

Multi-target Parallel Processing Approach for Gene-to-structure Determination of the Influenza Polymerase PB2 Subunit

Published on: June 28, 2013

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Structure-Guided Design of Affinity/Covalent-Bond Dual-Driven Inhibitors Targeting the AMP Site of FBPase

Hongxuan Cao1, Zeyue Huang1, Zheng Liu1

  • 1State Key Laboratory of Green Pesticide, College of Chemistry, Central China Normal University, Wuhan 430079, China.

Journal of Medicinal Chemistry
|November 9, 2024
PubMed

Insights

New dual-driven inhibitors target Fructose-1,6-bisphosphatase (FBPase), a key enzyme in diabetes and cancer. Covalent binding to C179 enhances long-lasting hypoglycemic effects, offering a promising drug development strategy.

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Pharmacology

Background:

  • Fructose-1,6-bisphosphatase (FBPase) is a significant therapeutic target for cancer and type II diabetes.
  • Existing FBPase inhibitors targeting the AMP allosteric site exhibit limited selectivity, leading to potential adverse effects.

Purpose of the Study:

  • To design and develop novel affinity/covalent-bond dual-driven inhibitors for FBPase.
  • To enhance inhibitor selectivity and efficacy by targeting the AMP pocket and a neighboring cysteine residue (C179).

Main Methods:

  • Utilized pharmacophore knowledge of the FBPase AMP pocket and C179.
  • Employed a cysteine-targeting reactivity warhead screen followed by structural optimization.
  • Confirmed direct FBPase targeting in hepatic cells using pull-down and Western Blotting assays.
  • Determined the binding mechanism via X-ray cocrystallography and Cov_DOX calculations.

Main Results:

  • Designed dual-driven inhibitors demonstrating potent FBPase inhibition.
  • X-ray crystallography revealed hydrogen bonding and π-π stacking as key binding interactions.
  • Covalent binding to C179 was confirmed, contributing to sustained hypoglycemic effects.
  • Inhibitors showed promising long-lasting hypoglycemic effects.

Conclusions:

  • Affinity/covalent-bond dual-driven inhibitors represent a promising strategy for FBPase-targeted drug development.
  • The developed inhibitors offer a potent approach for treating diseases associated with FBPase activity.
  • This study provides a foundation for developing novel therapeutics targeting AMP-associated proteins.

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