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PDBsum entry 3f4x
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References listed in PDB file
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Key reference
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Title
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Carbonic anhydrase inhibitors. Comparison of chlorthalidone and indapamide X-Ray crystal structures in adducts with isozyme ii: when three water molecules and the keto-Enol tautomerism make the difference.
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Authors
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C.Temperini,
A.Cecchi,
A.Scozzafava,
C.T.Supuran.
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Ref.
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J Med Chem, 2009,
52,
322-328.
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PubMed id
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Abstract
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Thiazide diuretics inhibit all mammalian isoforms of carbonic anhydrase (CA, EC
4.2.1.1) with a different profile as compared to classical inhibitors. Acting as
moderate-weak inhibitors of CA II and CA I, chlorthalidone and indapamide
considerably inhibit other isozymes among the 16 CAs present in vertebrates.
These compounds show a different behavior against CAs I and II, with
chlorthalidone being 18.3 times more potent against CA II and 150 times more
potent against CA I, as compared to indapamide. In the X-ray crystal structures
of the CA II-chlorthalidone adduct three active site water molecules interacting
with the inhibitor scaffold were observed that lack in the corresponding
indapamide adduct. Chlorthalidone bound within the active site is in an enolic
tautomeric form, with the OH moiety participating in two strong hydrogen bonds
with Asn67 and a water molecule. This binding mode may be exploited for
designing better CA II inhibitors.
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