Structural insight into the inhibition of carbonic anhydrase by the COX-2-selective inhibitor polmacoxib (CG100649)

Hyun Tae Kim, Hyunju Cha, Kwang Yeon Hwang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Polmacoxib is not only a selective COX-2 inhibitor but also a potent inhibitor of carbonic anhydrases (CAs). Both CA I and CA II are highly expressed in the GI tract and kidneys, organs that are also thought to be the sites at which selective COX-2 inhibitors show their side effects. By inhibition assays, we show that both CA I and CA II are strongly inhibited by polmacoxib, while CA II also demonstrates direct competition with COX-2. To understand, at the molecular level, how polmacoxib interacts with CA I and II, we solved the first crystal structures of CA I and CA II in complex with polmacoxib, at 2.0 Å and 1.8 Å, respectively. Interestingly, three polmacoxib molecules bind to the active site of CA I, whereas only one molecule binds CA II. In the active site, the three molecules of polmacoxib organize itself along hydrophobic interaction as “stack-on-formation”, and fully occupy a cone-shaped active pocket in CA I. The binding mode of polmacoxib to CA II was found different than its binding to celecoxib and valdecoxib. Our results provide structural insight into inhibition of CA I and CA II by polmacoxib, to assess its potential clinical efficacy.

Original languageEnglish
Pages (from-to)1-6
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume478
Issue number1
DOIs
Publication statusPublished - 2016 Sep 9

Fingerprint

Carbonic Anhydrase II
Carbonic Anhydrase I
Carbonic Anhydrases
Cyclooxygenase 2 Inhibitors
Celecoxib
Molecules
Catalytic Domain
Carbonic Anhydrase Inhibitors
CG100649
Hydrophobic and Hydrophilic Interactions
Gastrointestinal Tract
Cones
Assays
Crystal structure
Kidney

Keywords

  • CA I
  • CA II
  • COX-2 inhibitor
  • Crystal structure
  • Polmacoxib

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Structural insight into the inhibition of carbonic anhydrase by the COX-2-selective inhibitor polmacoxib (CG100649). / Kim, Hyun Tae; Cha, Hyunju; Hwang, Kwang Yeon.

In: Biochemical and Biophysical Research Communications, Vol. 478, No. 1, 09.09.2016, p. 1-6.

Research output: Contribution to journalArticle

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