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.
Keywords: Nicotinic acid, QSAR, docking, carbonic anhydrase, hummel–dreyer.
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