3D-QSAR studies of indole derivatives as phosphodiesterase IV inhibitors.

The 3D-QSAR studies of some indole derivatives as phosphodiesterase (PDE) type IV inhibitors was performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The global minimum energy conformer of the template molecule, 3 the most active molecule of the series, was obtained by simulated annealing method and used to build the structures of the molecules in the dataset. The CoMFA model produced statistically significant results with cross-validated and conventional correlation coefficients of 0.494 and 0.986 respectively. The combination of steric, electrostatic and hydrophobic fields in CoMSIA gave the best results with cross-validated and conventional correlation coefficients of 0.541 and 0.967 respectively. The predictive ability of CoMFA and CoMSIA were determined using a test set of seven indole derivatives giving predictive correlation coefficients of 0.56 and 0.59 respectively indicating good predictive power. Further, the robustness of the models was verified by bootstrapping analysis. Based upon the information derived from CoMFA and CoMSIA, we have identified some key features that may be used to design new indole derivatives and predict their PDE IV affinities prior to synthesis.