4D-QSAR analysis and pharmacophore modeling: Electron conformational- genetic algorithm approach for penicillins

Abstract

4D-QSAR studies were performed on a series of 87 penicillin analogues using the electron conformational-genetic algorithm (EC-GA) method. In this EC-based method, each conformation of the molecular system is described by a matrix (ECMC) with both electron structural parameters and interatomic distances as matrix elements. Multiple comparisons of these matrices within given tolerances for high active and low active penicillin compounds allow one to separate a smaller number of matrix elements (ECSA) which represent the pharmacophore groups. The effect of conformations was investigated building model 1 and 2 based on ensemble of conformers and single conformer, respectively. GA was used to select the most important descriptors and to predict the theoretical activity of the training (74 compounds) and test (13 compounds, commercial penicillins) sets. The model 1 for training and test sets obtained by optimum 12 parameters gave more satisfactory results (Rtraining2 = 0.861, SEtraining = 0.044, Rtest2 = 0.892, SEtest = 0.099, q2 = 0.702, qext12 = 0.777 and qext22 = 0.733) than model 2 (Rtraining2 = 0.774, SE training = 0.056, Rtest2 = 0.840, SEtest = 0.121, q 2 = 0.514, qext12 = 0.641 and qext22 = 0.570). To estimate the individual influence of each of the molecular descriptors on biological activity, the E statistics technique was applied to the derived EC-GA model. © 2011 Elsevier Ltd. All rights reserved.