Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 20, Issue 2, Pages 474-478Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.11.124
Keywords
Carbonic anhydrase; Anion inhibitor; Trithiocarbonate; Urea; Sulfonamide; X-ray crystallography
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Funding
- European Union
- MIUR/FIRB [RBNE03PX83_001]
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Trithiocarbonate (CS32-) inhibits with low micromolar affinities several mammalian carbonic anhydrases, CAs, EC 4.2.1.1 [Innocenti et al., Bioorg. Med. Chem. Lett. 2009, 19, 1855]. Here we report the X-ray crystal structure of the hCA II-trithiocarbonate adduct. Trithiocarbonate is monodentately bound to the Zn(II) ion and makes several hydrogen bonds with Thr199 and two water molecules from the enzyme active site. Its binding is different from that of ureate, another small inhibitor isosteric with trithiocarbonate but somehow mimicks the binding of the SO2NH moiety present in the sulfonamide inhibitors and is similar to that of bicarbonate. Compounds incorporating this new zinc-binding group, CS2-, may thus lead to new classes of potent inhibitors. (C) 2009 Elsevier Ltd. All rights reserved.
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