Inhibition of mammalian carbonic anhydrases I-XIV with grayanotoxin III: solution and in silico studies.

Grayanotoxin III (GTX3) was investigated for inhibition of all catalytically active mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms, i.e. CA I to CA XIV. It showed micromolar inhibition (KIs of 8.01 and 6.13 µM) for cytosolic isoforms CA I and II, respectively. GTX3 showed a submicromolar inhibition (KIs in the range of 0.51-2.15 µM) for the remaining cytosolic (CA III, VII and XIII), membrane-associated/transmembrane (CA IV, IX, XII and XIV), mitochondrial (CA VA and CA VB) and secreted (CA VI) isoforms. This inhibition profile is very different from that of the sulfonamide CA inhibitors (CAIs), which possess different clinical applications. A molecular docking study for GTX3 within the active sites of CA I and II assisted to the understanding of molecular mechanism of the ligand. The interesting inhibition profile, coupled with various possibilities of interacting with the enzyme active site make this family of natural compounds attractive leads for designing novel chemotypes acting as CAIs.