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

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 (hCA-IX) isozyme, based upon the crystal structure of murine CA-XIVA (PDB CODE 1RJ5) was performed, as...

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Bibliographic Details
Published in:Indian journal of biochemistry & biophysics 2010-08, Vol.47 (4), p.234-242
Main Authors: Akula, N V Murali Krishna, Kumar, Surendra, Singh, Vineet, Tiwari, Meena
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Carbonic Anhydrase Inhibitors - chemistry
Crystallization
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Electrons
Humans
Inhibitory Concentration 50
Models, Chemical
Models, Statistical
Molecular Sequence Data
Protein Isoforms
Quantitative Structure-Activity Relationship
Thiadiazoles - chemistry
Thiadiazoles - pharmacology
Triazoles - chemistry
Triazoles - pharmacology
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Summary: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 (hCA-IX) 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 (> or = 0.945 & > or = 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.
ISSN:0301-1208