Mechanisms of action of carbonic anhydrase inhibitors: Compounds that bind “out of the binding site” and compounds with an unknown mechanism of action

So far, the design of human carbonic anhydrase (CA) inhibitors has been easily driven by the introduction of specific zinc-binding groups (ZBGs) (primary and secondary sulfonamides and their bioisosteres, dithiocarbamates, phosphonates, hydroxamic acids, and so on), which directly or indirectly block the enzyme-mediated catalytic CO2 hydration. All these inhibitors have been elegantly characterized by X-ray diffraction studies of hCA II-inhibitor adducts. The results led to the discovery of several drug candidates potent and selective for clinical purposes. Conversely, the most exciting innovation was the proposal of an alternative mechanism of inhibition targeting the proton shuttle His64 out of the binding site. Moreover, new chemotypes without the above-described moieties are emerging as endowed with an unknown mechanism of interaction. New scenarios could be observed within these scaffolds to finely modulate CA activity.