Pharmacophore generation and atom based 3D-QSAR of quinoline derivatives as selective phosphodiesterase 4B inhibitors

Abstract

Phosphodiesterase 4B (PDE4B) hydrolyses cyclic adenosine monophosphate (cAMP) and thus regulates its intracellular levels. The enzyme has been proposed as a potential drug target against diseases like inflammation and chronic obstructive pulmonary disease. But use of current PDE4B inhibitors is limited due to dose-dependent nausea and vomiting. Adverse effects associated with current PDE4B inhibitors are possibly results of PDE4D inhibition, a highly similar homolog of PDE4B. Here we considered quinoline analogs and applied ligand-based pharmacophore and atom based 3D-QSAR modeling with structure-based docking and ADME approach. A 5-point pharmacophore model was developed and used to derive a predictive 3D-QSAR model for the studied dataset. The obtained r² and q² values were 0.96 and 0.91, respectively. The result suggested that the generated 3D-QSAR model is reliable and can be considered for PDE4B activity prediction. Further, a pharmacophore model was employed for virtual screening to identify potent PDE4B inhibitors. The selective ligands for PDE4B were identified through docking and prime binding energy analysis of ligands in both PDE4B and PDE4D. ADME analysis was performed to confirm the drug ability of the selective ligand. To validate docking results, a molecular dynamics simulation was performed for PDE4B complexed with a top scoring ligand, AQ-390/42425549. AQ-390/42425549-PDE4B interactions reported in MD analysis were consistent with the docking results. All the hit molecules were procured and biologically evaluated for percentage inhibition of PDE4B and PDE4D in in vitro enzymatic assays. Among the total of thirteen molecules that were active against PDE4B, ten were selective with little PDE4D inhibition.