Abstract
Type 4 cAMP phosphodiesterase (PDE4) inhibitors show a broad spectrum of anti-inflammatory effects in almost all kinds of inflamed cells, by an increase in cAMP levels which is a pivotal second messenger responsible for various biological processes. These inhibitors are now considered as the potential drugs for treatment of chronic inflammatory diseases. However, some recently marketed inhibitors e.g., roflumilast, have shown adverse effects such as nausea and emesis, thus restricting its use. In order to identify novel PDE4 inhibitors with improved therapeutic indexes, a highly correlating (r = 0.963930) pharmacophore model (Hypo1) was established on the basis of known PDE4 inhibitors. Validated Hypo1 was used in database screening to identify chemical with required pharmacophoric features. These compounds are further screened by using the rule of five, ADMET and molecular docking. Finally, twelve hits which showed good results with respect to following properties such as estimated activity, calculated drug-like properties and scores were proposed as potential leads to inhibit the PDE4 activity. Therefore, this study will not only assist in the development of new potent hits for PDE4 inhibitors, but also give a better understanding of their interaction with PDE4. On a wider scope, this will be helpful for the rational design of novel potent enzyme inhibitors.
Highlights
Type 4 cAMP-specific phosphodiesterase (PDE4) are a family of low km 3',5'-cyclic adenosine monophosphatespecific phosphodiesterases containing more than 20 isozymes encoded by four genes (PDE4A, PDE4B, PDE4C, and PDE4D) in mammals [1]
Pharmacophore modeling A set of ten pharmacophore models was generated by a training set containing 28 compounds
The correlation values of the generated pharmacophore models were greater than 0.91, and the values for the first three pharmacophore models were even higher, i.e., above 0.950. These results implied the capability of the pharmacophore model to predict the activity of the training set compounds
Summary
Type 4 cAMP-specific phosphodiesterase (PDE4) are a family of low km 3',5'-cyclic adenosine monophosphate (cAMP)specific phosphodiesterases containing more than 20 isozymes encoded by four genes (PDE4A, PDE4B, PDE4C, and PDE4D) in mammals [1]. PDE4s are taken as critical regulators of intracellular cAMP levels, cAMP signaling, and signal compartmentalization by their wide tissue distribution as well as differential expression and regulation among various cell types [1]. Many PDE4 inhibitors have showed remarked anti-inflammatory potential, by increasing cAMP levels. We successfully used pharmacophore modeling, database screening, and molecular docking approaches in identifying lead candidates to be used in potent PDE4 inhibitor design and thereby devising a new class of safer and effective anti-inflammatory agents
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