A perspective on quantitative structure–activity relationships and carbonic anhydrase inhibitors

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are wide-spread enzymes, present in mammals in at least 15 different isoforms. The 12 catalytically active isoforms play important physiological and pathophysiological functions and are strongly inhibited by aromatic/heterocyclic sulfonamides, sulfamides and sulfamates, among others. The catalytic and inhibition mechanisms of these enzymes are understood in great detail, and this greatly helped the design of potent inhibitors, some of which possess important clinical applications as antiglaucoma drugs, or in the management of some neuromuscular disorders. A recent discovery is connected with the involvement of CAs and their sulfonamide inhibitors in cancer: many potent CA inhibitors were shown to inhibit the growth of several tumour cell lines in vitro and in vivo, thus constituting interesting leads for developing novel antitumour therapies. The field of quantitative structure–activity relationship (QSAR), formalised by Hansch and others in the early 1960s, is the discovery of empirical relationships between the chemical structure of drugs and their biological activity. The emphasis is on empirical. Extending a QSAR to drugs other than those used to formulate it is always a new hypothesis, and although these extensions are often successful, it should be no cause for surprise if they break down in particular cases. With CA, as with other targets, the descriptor variables that have been used include topological indices, physical properties such as solvent partition coefficients and Hammett constants from reaction rate studies, and quantum theoretical parameters, such as orbital energies, atomic charges, polarisabilities and recently the orientation of nodes in π-orbitals. This review deals only with the physical and quantum theoretical descriptors.

Keywords::

• carbonic anhydrase inhibitor
• correlation
• QSAR
• quantum theoretical
• regression