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Related Concept Videos

Enzyme Inhibition01:30

Enzyme Inhibition

Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
Drug-Receptor Bonds01:25

Drug-Receptor Bonds

Drug-receptor bonds are formed through various chemical forces when drugs interact with target cells. Covalent bonds, strong and irreversible, are exemplified by DNA-alkylating anticancer agents that inhibit cell division. However, such irreversible drug binding lacks selectivity and can modify the DNA of the surrounding healthy cells. Covalent binding often contributes to tissue toxicity, as seen with chloroform and paracetamol metabolites binding to the liver, causing hepatotoxicity.
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Inhibitors of Bacterial DNA Synthesis01:28

Inhibitors of Bacterial DNA Synthesis

Bacterial pathogens depend on precise and efficient DNA replication to sustain infection. Two type II topoisomerases—DNA gyrase and topoisomerase IV—are critical to this process, as they resolve DNA supercoiling and unlink chromosomes during replication. Fluoroquinolones, synthetic derivatives of quinolones, exploit this mechanism by stabilizing the transient DNA–enzyme cleavage complex, preventing strand religation, and causing lethal double-strand breaks. These antibiotics are selectively...
Valence Bond Theory02:42

Valence Bond Theory

Coordination compounds and complexes exhibit different colors, geometries, and magnetic behavior, depending on the metal atom/ion and ligands from which they are composed. In an attempt to explain the bonding and structure of coordination complexes, Linus Pauling proposed the valence bond theory, or VBT, using the concepts of hybridization and the overlapping of the atomic orbitals. According to VBT, the central metal atom or ion (Lewis acid) hybridizes to provide empty orbitals of suitable...
Metal-Ligand Bonds02:51

Metal-Ligand Bonds

The hemoglobin in the blood, the chlorophyll in green plants, vitamin B-12, and the catalyst used in the manufacture of polyethylene all contain coordination compounds. Ions of the metals, especially the transition metals, are likely to form complexes.
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Covalent Fragment Screening Using the Quantitative Irreversible Tethering Assay
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Published on: February 28, 2025

Bivalent enzyme inhibitors discovered using dynamic covalent chemistry.

Alexandra J Clipson1, Venugopal T Bhat, Iain McNae

  • 1School of Chemistry, University of Edinburgh, King's Buildings, West Mains Rd., Edinburgh, UK.

Chemistry (Weinheim an Der Bergstrasse, Germany)
|July 12, 2012
PubMed
Summary

A novel bivalent dynamic covalent chemistry (DCC) system selectively targets homodimeric glutathione-S-transferase (GST) enzymes. This approach bridges binding sites, yielding selective nanomolar affinity compounds for cancer and tropical disease targets.

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Area of Science:

  • Medicinal Chemistry
  • Biochemistry
  • Drug Discovery

Background:

  • Glutathione-S-transferases (GSTs) are crucial enzyme families involved in detoxification and disease pathways.
  • Targeting homodimeric GSTs presents a challenge due to their complex structure.

Purpose of the Study:

  • To design and validate a bivalent dynamic covalent chemistry (DCC) system for selective inhibition of homodimeric GSTs.
  • To explore the potential of DCC in interrogating multiple binding sites on dimeric proteins.

Main Methods:

  • Development of dynamic covalent libraries (DCLs) utilizing aniline-catalyzed acylhydrazone exchange.
  • Design of bivalent hydrazides and glutathione-conjugated aldehydes to bridge GST binding sites.
  • Templating DCLs with various GST isozymes, including M class and Schistosoma japonicum (Sj) GSTs.

Main Results:

  • The DCC system demonstrated compatibility and high responsiveness to GST templating.
  • Selective, nanomolar affinity compounds were achieved, with a K(i) of 61 nM for mGSTM1-1.
  • Successful simultaneous interrogation of binding sites on different subunits of dimeric GSTs.

Conclusions:

  • DCC is a viable strategy for developing selective inhibitors of homodimeric GSTs.
  • This approach offers a powerful tool for drug discovery against GSTs implicated in cancer and tropical diseases.
  • The study highlights the potential of DCC for targeting dimeric protein complexes.