X-Ray Crystallography of Carbonic Anhydrase Inhibitors and Its Importance in Drug Design

The carbonic anhydrase (CA) family was recently shown to be a target for the drug design of inhibitors with various medicinal chemistry applications. However, despite massive research and development efforts, none of the presently available clinically used CA inhibitors shows selectivity for a specific isozyme, although their affinity for most of them varies to a large extent. X-Ray crystallography is a very useful tool for the rational drug design of more selective enzyme inhibitors, and recently a large number of X-ray crystallographic studies on different alpha-CA isozymes and CA-inhibitor complexes provided a scientific basis for the rational design of more selective such inhibitors. In this comprehensive review we summarize in a comparative manner structural aspects of CA-inhibitor interactions and recapitulate how 3D structure of CA-inhibitor complexes, as well as the inhibition profiles of compounds screened on all human CA isozymes, can be used to design such inhibitors with better pharmacological properties.