Quantitative structure–activity relationship and design of polysubstituted quinoline derivatives as inhibitors of phosphodiesterase 4

Abstract

2D quantitative structure–activity relationships (2D QSAR) and hologram quantitative structure–activity relationship (HQSAR) studies were performed on a series of polysubstituted quinoline derivatives as inhibitors of phosphodiesterase 4 (PDE4). The dataset was divided into training set and test set by K-means clustering. 2D QSAR study was carried out using stepwise linear regression analysis, replacement method and enhanced replacement method. Statistically significant equations with high correlation coefficient (R 2 = 0.817) and low standard deviation (SD = 0.272) were obtained. The robustness of the models was confirmed with the help of leave one out cross validation (R cv 2 = 0.740), Y scrambling (R 2 = 0.374), and by predicting the activities of test molecules (R pred 2 = 0.627). A good correlation of topology, steric and polar features of polysubstituted quinoline derivatives with the PDE4 inhibitory activity was achieved. HQSAR calculations were carried out using various combinations of fragment size, hologram length and fragment type. The best HQSAR model was obtained with an R 2 value of 0.952 and $$ R_{\text{cv}}^{2} $$ value of 0.783. The test-set of molecules was predicted by the HQSAR model. The results of 2D QSAR and HQSAR studies were used to design new molecules and to predict their activity using the developed models.