Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors

Abstract

Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma andchronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known toreduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. Thismakes the development of PDE4B subtype selective inhibitors a desirable research goal. Toachieve this goal, ligand based pharmacophore modeling approach is employed. Separatepharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGenalgorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines,2-arylpyrimidines, and triazines skeleton. Suitable training and test sets were created usingthe molecules as per the guidelines available for HypoGen program. Training set was used forhypothesis development while test set was used for validation purpose. Fisher validation wasalso used to test the significance of the developed hypothesis. The validated pharmacophorehypotheses for PDE4B and PDE4D inhibitors were used in sequential virtual screening of zincdatabase of drug like molecules to identify selective PDE4B inhibitors. The hits were screenedfor their estimated activity and fit value. The top hit was subjected to docking into the activesites of PDE4B and PDE4D to confirm its selectivity for PDE4B. The hits are proposed to beevaluated further using in-vitro assays.