Exploring the multiple binding modes of inhibitors to carbonic anhydrases for novel drug discovery.

The spacious active site cavity of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) shows a great versatility for a variety of binding modes for modulators of activity, inhibitors, and activators, some of which are clinically used drugs. There are at least four well-documented CA inhibition mechanisms and the same number of binding modes for CA inhibitors (CAIs), one of which superposes with the binding of activators (CAAs). They include (i) coordination to the catalytic metal ion; (ii) anchoring to the water molecule coordinated to the metal ion; (iii) occlusion of the active site entrance; and (iv) binding outside the active site. A large number of chemical classes of CAIs show these binding modes explored in detail by kinetic, crystallographic, and other techniques. The tail approach was applied to all of them and allowed many classes of highly isoform-selective inhibitors. This is the subject of our review. All active site regions of CAs accommodate inhibitors to bind, which is reflected in very different inhibition profiles for such compounds and the possibility to design drugs with effective action and new applications, such as for the management of hypoxic tumors, neuropathic pain, cerebral ischemia, arthritis, and degenerative disorders.