Design of zinc binding functions for carbonic anhydrase inhibitors.
Zinc ion plays a crucial role in the protein's functions and is linked to a variety of physiological processes. It constitutes an essential component of numerous enzymes especially carbonic anhydrase (CAs, EC 4.2.1.1), a pharmaceutically-important metalloprotein which catalyses efficiently the reversible hydration of carbon dioxide to bicarbonate with discharge of a proton. The potential therapeutic applications of selective carbonic anhydrase inhibitors has become an important challenge over the last few years, as some isoforms of this enzyme on the 16 described in higher vertebrates have been found to be involved in important pathologies such as cancer, obesity and ophthalmologic diseases. Coordination of the inhibitor with the zinc ion present in the active site is an important determinant which has to be taken into consideration for the design of isozyme-specific and organ-selective inhibitors. Besides the well known sulfonamide function, others zinc binding groups have been described constituting a new platform for the development of novel pharmacological agents. In this review, recent studies on the discovery of new zinc binding function will be discussed.
Winum
Jean-Yves
JY
Institut des Biomolécules Max Mousseron UMR 5247 CNRS-UM1-UM2 Bâtiment de Recherche Max Mousseron, Ecole Nationale Supérieure de Chimie de Montpellier, 8 rue de l'Ecole Normale, 34296 Montpellier Cedex, France. jean-yves.winum@univ-montp2.fr
Scozzafava
Andrea
A
Montero
Jean-Louis
JL
Supuran
Claudiu T
CT
D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D002256:Carbonic Anhydrases / Q000737:chemistry / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D011485:Protein Binding / Q000502:physiology; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry / Q000378:metabolism*
D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D015032:Zinc