Modified Hummel-Dreyer Method and Molecular Modeling Studies Identified Nicotinic Acid Analogues as Carbonic Anhydrase III Ligands

The anti-hyperlipidemic effect of nicotinic acid and its ability to overexpress PPARγ combined with the recently elucidated role of carbonic anhydrase III (CAIII) in of PPARγ expression, suggested the possibility that nicotinic acid inhibits CAIII. To validate this hypothesis we docked nicotinic acid into the binding pocket of CAIII. Apparently, nicotinic acid shared at least four critical binding interactions with potent CAIII inhibitor. Subsequent experimental validation using Hummel– Dreyer method indicated that nicotinic acid indeed inhibited the enzymatic activity of CAIII with an Ki value of 203 μM. Additional eighteen nicotinic acid analogues were tested and seven compounds were more active than nicotinic acid with ki values ranging 69.7- 115.2 μM. Docking studies and QSAR analysis were applied to explore the structural requirements for inhibiting CAIII and to build self-consistent and predictive model. Our findings strongly suggest that CAIII inhibition is at least one of the mechanisms for the reported anti-hyperlipidemic properties of nicotinic acid.