Molecular Modeling and QSAR Analysis of Some 4,5-Dichloroimidazolyl-1,4-DHP- Based Calcium Channel Blockers
B. Hemmateenejada,b,*, R. Miria,c, N. Edrakia, M. Khoshneviszadeha and A. Shafieec
aMedicinal & Natural Products Chemistry Research Center, Shiraz University of Medical Science, Shiraz, Iran
bChemistry Department, Shiraz University, Shiraz, Iran
cDepartment of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
(Received 20 September 2006, Accepted 5 November 2006)
The effects of the structural features of some 4,5-dichloroimidazolyl-1,4-dihydropyridine on their calcium channel antagonist activity have been studied using molecular modeling and quantitative structure activity-relationship analysis. Both symmetrical and asymmetrical dihydropyridine derivatives were used. AM1 semi-empirical quantum chemical calculation was used to find the optimum 3-D geometry of the molecules. Four different sets of descriptors, including chemical, topological, quantum chemical and substituent constant, were then calculated for each molecule. For each set of descriptors, the best multilinear QSAR equations were obtained by the stepwise variable selection method using leave-one-out cross-validation as selection criterion. Separate QSAR models were first obtained for symmetrical and asymmetrical derivatives, after which a general model was proposed for the entire set of molecules. This model has root mean square error of 0.45 and reproduces more than 82% of the variances in the calcium channel antagonist activity data. The sum of the negative charges, the energy of the highest occupied molecular orbital, molecular volume and the least negative charge were identified as the most significant descriptors.
Keywords: QSAR, Molecular modeling, Dihydropyridine, Calcium channel antagonist