3D-QSAR of Novel Phosphodiesterase-4 Inhibitors by Genetic Function Approximation

Anand      V. Raichurkar; Ujashkumar      A. Shah; Vithal      M. Kulkarni

doi:10.2174/157340611797928352

Abstract

Phosphodiesterase-4 (PDE 4) enzyme has emerged as an invaluable target for the treatment of asthma, chronic obstructive pulmonary disease and rheumatoid arthritis. These findings have generated widespread interest in PDE-4 inhibitors as a potential molecular target for the development of new anti-inflammatory drugs. A series of N-substituted cistetra- and cis-hexahydrophthalazinone derivatives have been reported as novel, selective PDE-4 inhibitors with potent anti-inflammatory activity. In order to gain further insights into the structural requirements of novel series of Nsubstituted cis-tetra and cis-hexahydrophthalazinone derivatives as PDE-4 inhibitors, a three-dimensional quantitative structure activity relationship (3D-QSAR) was performed using Genetic Function Approximation (GFA). The QSAR model was generated using a training set of 45 molecules and the predictive ability of the resulting each model was assessed using a test set of 9 molecules. The internal and external consistency of final QSAR model was 0.675 and 0.750 respectively. Analysis of results from the present QSAR study indicates that shape and structural descriptors strongly govern the PDE-4 enzyme inhibitory activity. This QSAR study highlights the structural features required for PDE-4 enzyme inhibition and may be useful for design of potent PDE-4 inhibitors.

Keywords: 3D-QSAR, anti-inflammatory agent, asthma, cis-tetra, cis-hexahydrophthalazinone, GFA, PDE-4 inhibitors, Phosphodiesterase-4, anti-inflammatory drugs, pulmonary disease