Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors

Introduction: Carbonic anhydrases (CAs, EC 4.2.1.1) exist as five genetically distinct families (alpha, beta, gamma, delta and zeta) in organisms all over the phylogenetic tree. Due to the ubiquity of such enzymes, the selective inhibition and polypharmacology of inhibitors is an important aspect of all drug design campaigns. There are several classes of CA inhibitors (CAIs): i) metal ion binders (sulfonamides and their isosteres [sulfamates/sulfamides], dithiocarbamates, mercaptans and hydroxamates); ii) compounds anchoring to the zinc-coordinated water molecule/hydroxide ion (phenols, carboxylates, polyamines, esters and sulfocoumarins) and iii) coumarins and related compounds which apparently bind even further away from the metal ion. Areas covered: The authors rationalize the drug design strategies of inhibitors belonging to the first two classes, based on recent X-ray crystallographic data. More precisely, this is achieved by analyzing how the hydrophobic and hydrophilic halves of the enzyme active site interact with inhibitors. This task has been eased by the recent report of beta-CA-like enzymes possessing carbon disulfide and carbonyl sulfide hydrolase activities, respectively, allowing the authors to propose a general approach of structure-based drug design of CAIs. Expert opinion: Although amazing progress has been made in the structure-based drug design of CAIs, this field is still in progress, with many constantly emerging new findings. Indeed, several new such enzymes were discovered and characterized recently and novel chemotypes were explored for finding compounds with a better inhibition profile. It is anticipated that this will continue to be one of the main frontiers in the search of pharmacologically relevant enzyme inhibitors.