3BL0

Carbonic anhydrase inhibitors. Interaction of 2-N,N-Dimethylamino-1,3,4-thiadiazole-5-methanesulfonamide with twelve mammalian isoforms: kinetic and X-Ray crystallographic studies

Summary for 3BL0

• Entry DOI: 10.2210/pdb3bl0/pdb
• Related: 2EU2 2EU3 3BL1
• Descriptor: Carbonic anhydrase 2, ZINC ION, 1-[5-(dimethylamino)-1,3,4-thiadiazol-2-yl]methanesulfonamide, ... (5 entities in total)
• Functional Keywords: carbonic anhydrase, inhibitors, sulfonamide, acetylation, cytoplasm, disease mutation, lyase, metal-binding, polymorphism, zinc, lyase(oxo-acid)
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29898.46

Authors

Temperini, C.,Supuran, C.T.,Blackburn, G.M. (deposition date: 2007-12-10, release date: 2008-01-22, Last modification date: 2024-02-21)

Primary citation

Temperini, C.,Cecchi, A.,Boyle, N.A.,Scozzafava, A.,Cabeza, J.E.,Wentworth, P.,Blackburn, G.M.,Supuran, C.T.
Carbonic anhydrase inhibitors. Interaction of 2-N,N-dimethylamino-1,3,4-thiadiazole-5-methanesulfonamide with 12 mammalian isoforms: kinetic and X-ray crystallographic studies.
Bioorg.Med.Chem.Lett., 18:999-1005, 2008

PubMed Abstract: 2-N,N-Dimethylamino-1,3,4-thiadiazole-5-methanesulfonamide was tested for its interaction with the 12 catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isozymes, CA I-XIV. The compound is a potent inhibitor of CA IV, VII, IX, XII, and XIII (K(I)s of 0.61-39 nM), a medium potency inhibitor of CA II and VA (K(I)s of 121-438 nM), and a weak inhibitor against the other isoforms (CA III, VB, VI, and XIV), making it a very interesting candidate for situations in which a strong/selective inhibition of certain isozymes is needed. The crystal structure of the hCA II adduct of this sulfonamide revealed interesting interactions between the inhibitor and the enzyme which are quite different from those observed in the adducts of CA II with the structurally related aliphatic derivatives zonisamide, 2-amino-1,3,4-thiadiazolyl-5-difluoromethanesulfonamide, and 2-dimethylamino-5-[sulfonamido-(aminomethyl)]-1,3,4-thiadiazole reported earlier.

PubMed: 18162396
DOI: 10.1016/j.bmcl.2007.12.022

Experimental method

X-RAY DIFFRACTION (1.9 Å)