4D-QSAR STUDIES AND PHARMOCOPHORE MODELLING OF PHENYLPYRAZINE DERIVATIVES AS PHOSPHODIESTERASE 10A INHIBITORS BY EC-GA METHOD

ABSTRACTInthis work, we presents the results of pharmacophore identification andbioactivity prediction for phenylprazine analogues as class of PDE10Ainhibitors by means of Electron Conformational-Genetic Algorithm method1.EC-GA method was developed that combines EC and GA methods. 3D structures ofcompounds, conformational analysis and quantum chemical calculations have beenworked Spartan 10 software at Hartree Fock 3-21 G* level and water was used assolvent. Then the ECMC matrix was prepared that contains distances betweenatoms and mulliken charges for pharmacophore identification. Nonlinear leastsquare regression method and genetic algorithm were performed to predict thetheoretical activity. For cross validation and statistical analysis compoudswere classified training and test set. In this study 49 training, 24 test setwas used. For the predictive capabilities best subset of descriptors werecalculated for a range of 1-14 parameters at MATLAB software. Hence the modelattains a stable situation as optimum 10 parameter number. LOO-CV method hadbeen employed for the predictive ability of 4D-QSAR model. In addition toE-statistical method was used to determination of the effect selectedparameters. R2training, R2test, q2,q2ext1, q2ext2, q2ext3and con1, con2, con3 values are given respectively 0.865, 0.819, 0.808, 0.824,0.816, 0.819, 0.929,0.899, 0.920. Keywords:4D-QSAR, EC-GA, Phenylpyrazine, Pharmacophore