Diversely N-substituted benzenesulfonamides dissimilarly bind to human carbonic anhydrases: crystallographic investigations of N-nitrosulfonamides

Carbonic anhydrases (CAs) are a zinc metalloenzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and proton, pivotal for a wide range of biological processes. CAs are involved in numerous pathologies and thus represent valuable drug targets in the treatments of several diseases such as glaucoma, obesity, tumour, neuropathic pain, cerebral ischaemia, or as antiinfectives. In the last two decades, several efforts have been made to achieve selective CA inhibitors (CAIs) employing different drug design approaches. However, N-substitutions on primary sulphonamide groups still remain poorly investigated. Here, we reported for the first time the co-crystallisation of a N-nitro sulphonamide derivative with human (h) CA II pointing out the binding site and mode of inhibition of this class of CAIs. The thorough comprehension of the ligand/target interaction might be valuable for a further CAI optimisation for achieving new potent and selective derivatives.

Automated summary

Carbonic anhydrases (CAs) are important zinc metalloenzymes that catalyze the hydration of carbon dioxide. They play crucial roles in various biological processes and can be targeted for the treatment of diseases like glaucoma, obesity, and cancer. In this study, we report the co-crystallization of a N-nitro sulphonamide derivative with human CA II, revealing the binding site and mode of inhibition. This knowledge could aid in the development of more potent and selective CA inhibitors.