Pharmacophore Based Virtual Screening Approach to Identify Selective PDE4B Inhibitors

Document Type: Research article

Authors

1 Faculty of Pharmaceutical Sciences, UCSI University, No. 1, UCSI Heights, Jalan Menara Gading, Taman Connaught, 56000 Kuala Lumpur, Federal Territory of Kuala Lumpur, Kuala Lumpur, Malaysia.

2 Department of Chemistry, Faculty of Science, University of Malaya 50603, Kuala Lumpur, Malaysia

Abstract

Phosphodiesterase 4 (PDE4) has been established as a promising target in asthma and
chronic obstructive pulmonary disease. PDE4B subtype selective inhibitors are known to
reduce the dose limiting adverse effect associated with non-selective PDE4B inhibitors. This
makes the development of PDE4B subtype selective inhibitors a desirable research goal. To
achieve this goal, ligand based pharmacophore modeling approach is employed. Separate
pharmacophore hypotheses for PDE4B and PDE4D inhibitors were generated using HypoGen
algorithm and 106 PDE4 inhibitors from literature having thiopyrano [3,2-d] Pyrimidines,
2-arylpyrimidines, and triazines skeleton. Suitable training and test sets were created using
the molecules as per the guidelines available for HypoGen program. Training set was used for
hypothesis development while test set was used for validation purpose. Fisher validation was
also used to test the significance of the developed hypothesis. The validated pharmacophore
hypotheses for PDE4B and PDE4D inhibitors were used in sequential virtual screening of zinc
database of drug like molecules to identify selective PDE4B inhibitors. The hits were screened
for their estimated activity and fit value. The top hit was subjected to docking into the active
sites of PDE4B and PDE4D to confirm its selectivity for PDE4B. The hits are proposed to be
evaluated further using in-vitro assays.

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