X-ray Structural Analysis of Carbonic Anhydrase and Carborane-Based Inhibitors Complexes

Jiří Brynda^1,2, Pavel Mader^1,2, Václav Šícha³, Milan Fábry¹, Bohumír Grüner³, Petr Cígler², Pavlína Řezáčová^1,2

¹Institute of Molecular Genetics Academy of Sciences of the Czech Republic, v.v.i.

²Institute of Organic Chemistry and Biochemistry AS CR, v.v.i.

³Institute of Inorganic Chemistry, Academy of Sciences of the Czech Republic, v.v.i.

Human carbonic anhydrases (CA) are zinc metalloenzymes that play an important role in many physiological processes. To date, 15 human CA isozymes have been identified. Many experimental evidence also suggests involvement of CAs in various pathological processes, e.g. tumorigenicity, thus, many CA isozymes are recognized as diagnostic and therapeutic targets. About 30 CA inhibitors are used clinically as drugs. The traditional CA inhibitors contain a sulfonamide or sulfamide moiety that coordinates the zinc cation located in the CA catalytic site. Although the conical active site clefts of different human CA isoezymes are conserved, variations in aminoacid residues exist at the entrance to the active site. These surface pockets with different shape and hydrophobicity can be exploited to design specific inhibitors. With the help of manual molecular docking into the active site of CAII, we designed new molecule, which contains a sulfamide group connected to a carborane cluster intended to optimally fill the enzyme active site entry.