Pharmacophore modeling, 3DQSAR, and docking-based design of polysubstituted quinolines derivatives as inhibitors of phosphodiesterase 4, and preliminary evaluation of their anti-asthmatic potential

Abstract

3D QSAR models using 3D pharmacophore, CoMFA, and CoMSIA approaches were developed for a series of quinoline derivatives as PDE4 receptor antagonists. Hypogen method was used to engender the 3D pharmacophore model. The top scoring four feature pharmacophore models, Hypo1 contains one hydrogen-bond acceptor, two hydrogen-bond donors, and a hydrophobic feature. Hypo1 was validated using test set, Fischer’s randomization test, and screening of decoy set. CoMFA and CoMSIA models were developed using the alignment obtained by pharmacophore (Hypo1), substructure alignment, and by application of region focusing. Substructure alignment followed by region focusing provided the best CoMFA and CoMSIA models. Based on the results of 3D QSAR studies, some new molecules were designed and evaluated by Docking and Lipinski filters. The designed molecules were synthesized and two top scoring molecules were subjected to preliminary evaluation of their efficacy in treatment of asthma and COPD. The molecules demonstrated efficacy comparable to standard drugs in treatment of asthma and COPD.