Dithiocarbamates: a new class of carbonic anhydrase inhibitors. Crystallographic and kinetic investigations.
The zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) is inhibited by several classes of zinc-binders (sulfonamides, sulfamates, and sulfamides) as well as by compounds which do not interact with the metal ion (phenols, polyamines and coumarins). Here we report a new class of potent CA inhibitors which bind the zinc ion: the dithiocarbamates (DTCs). They coordinate to the zinc ion from the enzyme active site in monodentate manner and establish many favorable interactions with amino acid residues nearby. Several low nanomolar CA I, II and IX inhibitors were detected.
Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy.
Fabrizio
F
Carta
Mayank
M
Aggarwal
Alfonso
A
Maresca
Andrea
A
Scozzafava
Robert
R
McKenna
Claudiu T
CT
Supuran
D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry; D011487:Protein Conformation; D013859:Thiocarbamates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D013859:Thiocarbamates; D002256:Carbonic Anhydrases; D009584:Nitrogen