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Open Access research with a European policy impact...

The Strathprints institutional repository is a digital archive of University of Strathclyde's Open Access research outputs. Strathprints provides access to thousands of Open Access research papers by Strathclyde researchers, including by researchers from the European Policies Research Centre (EPRC).

EPRC is a leading institute in Europe for comparative research on public policy, with a particular focus on regional development policies. Spanning 30 European countries, EPRC research programmes have a strong emphasis on applied research and knowledge exchange, including the provision of policy advice to EU institutions and national and sub-national government authorities throughout Europe.

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First crystal structures of human carbonic anhydrase II in complex with dual aromatase-steroid sulfatase inhibitors

Lloyd, M D and Thiyagarajan, N and Ho, Y T and Woo, L W L and Sutcliffe, O B and Purohit, A and Reed, M J and Acharya, K R and Potter, B V L (2005) First crystal structures of human carbonic anhydrase II in complex with dual aromatase-steroid sulfatase inhibitors. BMC Biochemistry, 44 (18). pp. 6858-6866. ISSN 1471-2091

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Abstract

Carbonic anhydrase (CA) catalyzes the reversible hydration of carbon dioxide to hydrogen carbonate. The role of CA in maintaining pH balance has made it an attractive drug target for the treatment of cancer, and it has recently been implicated in the delivery of sulfamate-containing drugs. With the acceptance of steroid sulfatase as a target for hormone-dependent cancer, novel dual aromatase-steroid sulfatase inhibitors (DASIs) containing a sulfamate group are now being developed. In this study, we show that CA 11 is potently inhibited by several members of this class of inhibitor. The structures of CA 11 complexed with 4-[(4-O-sulfamoylbenzyi)(4-cyanophenyl)amino]-4H-[1,2,4]triazole (K-D = 84 ± 5 nM) and 4-[(3-bromo-4-0-sulfamoylbenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole (K-D = 454 ± 29 nM) are reported to 2.02 and 1.76 A, respectively. Both inhibitors ligate to the active site zinc(II) atom via their sulfamate nitrogen, while the rest of the molecule is contained within the hydrophobic binding pocket. Key protein residues include Val-121, Phe-131, Val-t35, Val-143, Leu-141, Leu- 198, Pro-202, and Leu-204. Despite being structurally similar, the two ligands experience different types of binding particularly in the sulfamate-containing aromatic ring and the opposite geometric arrangement of the triazole and cyanophenyl groups around the configurationally invertible central nitrogen atom. Small changes in inhibitor structure can cause large changes in binding to CA 11, and this underlines the importance of structure-based drug design with this enzyme and other isoforms relevant to potential anticancer therapy. Moreover, these results underpin the idea that binding to erythrocyte CA 11 may be a general method of stabilizing and delivering sulfamate-based drugs in vivo.