Advances in the structural annotation of human carbonic anhydrases and impact on future drug discovery

Introduction: Of the 15 human carbonic anhydrase (CA, EC 4.2.1.1) isoforms known to date, for 11 the crystal structure is known. Many different classes of CA inhibitors (CAIs) were reported in the last decade, with a wealth of inhibition mechanisms, where apart from the classical one, the inhibitors do not bind to the zinc ion from the active site. The zinc binders (sulfonamides, dithiocarbamates and their isosteres, thiols, selenols, carboxylates, hydroxamates, carbamates) are not isoform-selective inhibitors, but the specificity of action may be achieved by decorating their scaffolds with tails that interact with amino acids at the entrance of the active site. Areas covered: Herein, the authors review the advances in the structural annotation of human CAs. Furthermore, the authors look at the impact on drug discovery efforts as well as providing their expert perspectives. Expert opinion: CAs are a unique example among metalloenzymes for which all regions of their spacious active sites may be used for inhibitor/activator binding, leading to a variety of inhibition mechanisms and profiles for the many chemotypes modulating their activity. This is exploited for the drug design of increasingly efficient and isoform-selective inhibitors, useful for many pharmacological applications.