title: Structural insight into the inhibition of carbonic anhydrase by the COX-2-selective inhibitor polmacoxib (CG100649).
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.
authors.affiliation: Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul, 136-701, Republic of Korea.
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Kim
authors.affiliation: Division of Industrial Promotion Research, Korea Food Research Institute, 62 Anyangpangyo-ro 1201 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-746, Republic of Korea.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Cha
authors.affiliation: Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Anam-dong, Seongbuk-gu, Seoul, 136-701, Republic of Korea. Electronic address: chahong@korea.ac.kr.
authors.forename: Kwang Yeon
authors.initials: KY
authors.lastname: Hwang
mesh_terms: D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D018360:Crystallography, X-Ray; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000493:pharmacokinetics*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: C000599293:CG100649; D002257:Carbonic Anhydrase Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans; D013449:Sulfonamides; D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II
keywords: CA I; CA II; COX-2 inhibitor; Crystal structure; Polmacoxib