The choice of atomic charges calculation scheme in 3D-QSAR modelling of GSK-3β inhibition by paullones

Abstract

descriptors in the nodes of the threedimensional lat� tice surrounding these molecules. The energy of van der Waals and electrostatic interactions of a probe atom ( with the charge +1) with molecules of the training set (CoMFA) or the electrostatic, van der Waals, hydrophobic, and donor/acceptor similarity indices (CoMSIA) are used as descriptors. The equa� tion for activity prediction is derived using the partial least squares (PLS) method. The ability of graphic representation of PLS model coefficients is the advan� tage of the methods and allows the user to suggest sub� stitutions affecting activity and/or selectivity of the molecules. The electrostatic field rules to the intermolecular interactions and plays major role in CoMFA and CoMSIA modeling. The contribution of the electro� static field is estimated with the help of partial atomic charges of molecules under consideration. The suc� cess of a modeling study strongly depends on proper selection of an adequate method for calculation of atomic charges. Various parameters should be taken into account, such as the calculation time, geometri� cal parameters of molecules, the accuracy and signifi� cance of modeling results, and stability upon small changes of the geometrical parameters of the mole� cule. In this study different charge calculation schemes based on different combinations of the men� tioned parameters were used to build predictive mod� els with the aim to identify one or more schemes pos� sessing an optimal set of parameters for 3DQSAR modeling. The training set comprised of the compounds pre� viously used for CoMSIA modeling (9) along with small series of epoxidecontaining analogues (10). The total number of compounds in the training set was 77. Twentyeight compounds whose inhibitory activity was determined later (11) were used as an external test set. The inhibitory activity of all compounds was determined under identical conditions and expressed as