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Assays for Validating Histone Acetyltransferase Inhibitors
Published on: August 6, 2020
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Acipimox inhibits human carbonic anhydrases
Mattia Mori1, Claudiu T Supuran2
1Department of Biotechnology, Chemistry and Pharmacy, "Department of Excellence 2018-2022", University of Siena, Siena, Italy.
Journal of Enzyme Inhibition and Medicinal Chemistry
|February 10, 2022
Summary
Acipimox inhibits human carbonic anhydrase (hCA) enzymes, which are involved in fat production. This finding may help in designing new anti-obesity drugs targeting these enzymes.
Area of Science:
- Biochemistry
- Enzymology
- Medicinal Chemistry
Background:
- Acipimox is a nicotinic acid derivative used for hyperlipidemia.
- Its structure contains a carboxylic acid and N-oxide moiety.
- These functional groups are known to interact with carbonic anhydrase (CA).
Purpose of the Study:
- To investigate acipimox as a carbonic anhydrase inhibitor (CAI).
- To explore the inhibitory activity of acipimox against human CA (hCA) isoforms.
- To elucidate the binding mechanism of acipimox to hCA active sites.
Main Methods:
- In vitro enzyme inhibition assays.
- Computational methods including docking and molecular dynamics simulations.
Main Results:
- Acipimox demonstrated low micromolar CA inhibition against most catalytically active hCA isoforms (hCA I-XIV).
- Computational analysis suggested acipimox coordinates with the zinc ion via its carboxylate group.
- The N-oxide group forms hydrogen bonds with active site residues like His, Thr, or Gln, varying by isoform.
Conclusions:
- Acipimox is a potent inhibitor of various human carbonic anhydrase isoforms.
- The proposed binding mode provides insights into acipimox-hCA interactions.
- These findings could aid in designing novel CAIs with potential anti-obesity effects due to CA's role in lipogenesis.
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