Homology modeling and QSAR analysis of 1,3,4-thiadiazole and 1,3,4-triazole derivatives as carbonic anhydrase inhibitors

Abstract

Carbonic anhydrase (CA) inhibitors are very interesting target for designing anticancer (hypoxic) and antiglaucoma drugs. In the present study, a 3D homology modeling of human carbonic anhydrase-IX<i style=""> (</i>hCA-IX<i style="">)</i> isozyme, based upon the crystal structure of murine CA-XIVA (PDB CODE 1RJ5) was performed, as no experimental 3D structures are available. A homology model of hCA-IX was developed and validated. To explore the responsible physicochemical properties of 1,3,4-thiadiazole and 1,3,4-triazole derivatives for carbonic anhydrase inhibition, a quantitative structure activity relationship (QSAR) study was performed having hCA-II and hCA-IX inhibitory activity respectively. In hCA-II and hCA-IX inhibitory activities, four significant models with good correlations (<img src='http://www.niscair.res.in/jinfo/greaterequal.gif' border=0> 0.945 &amp; <img src='http://www.niscair.res.in/jinfo/greaterequal.gif' border=0> 0.926) were obtained; two models (models 1 and 3) were selected based on statistical criterion. The QSAR study revealed that in case of hCA-II, overall increase in size and volume of molecule, introduction of electropositive surfaces might increase the inhibitory activity, whereas in case of hCA-IX, decreasing the hydrophobicity and introduction of electron releasing substituents might increase the hCA-IX inhibitory activity.