Phosphodiesterases (PDEs) are responsible for the hydrolysis of cyclic nucleotides (cAMP and c-GMP). Cyclic
nucleotides are important intracellular secondary messengers in cell function, relaying the signals from hormones at
specific cell-surface receptors. An increase of cAMP due to the stimulation of adenylyl cyclase or the inhibition of PDEs
affects the activity of immune system and inflammatory cells. Thus, PDE4, a cAMP specific PDE, received much
attention as a target for the treatment of the diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD).
Pyrazolo[4,3-c]quinoline-3-one nucleus has attracted considerable attention recently as PDE4 receptor antagonists which
have shown remarkable therapeutic potential in the treatment of asthma and Chronic Obstructive Pulmonary Disease
(COPD). In the present study, three dimensional quantitative structure activity relationship (3D QSAR) approach using
CoMFA and CoMSIA was applied to a series of 2, 5-dihydropyrazolo [4, 3-c] quinoline-3-ones as PDE4 receptor
antagonists. For the purpose, 22 compounds from the series were used to develop and validate models. The robustness of
the model was confirmed with the help of leave one out cross-validation method, while the predictive ability of models
was tested using a test set containing three molecules. Novel compounds were designed on the basis of results of CoMFA
and CoMSIA studies. Designed compounds were evaluated by Docking and Lipinski filters. 3D-QSAR models with high
squared correlation coefficient of up to 0.9590 for CoMFA and 0.9740 for CoMSIA were established. Robustness of the
models is demonstrated by R2
cv values of up to 0.8600 and 0.8230 for CoMFA and CoMSIA, respectively. Predictive
ability of the models is reflected by R2
pred values of 0.865 and 0.926 for CoMFA and CoMSIA respectively. Predicted
activity of the designed molecules correlated well with the docking scores and the molecules also passed the Lipinski
filters. Developed models highlighted the importance of steric, electrostatic and hydrophobic properties of the molecules
for PDE 4 receptor affinity. The designed compounds may serve as lead for the development of newer PDE4 inhibitors
based on the 2, 5-dihydropyrazolo [4, 3-c] quinoline-3-one scaffold.
Phosphodiesterase, CoMFA, CoMSIA, k-means clustering, enhanced replacement method, replacement method,
School of Pharmaceutical Sciences, Shobhit University, Meerut, 250110, India.