Three-Dimensional Quantitative Structure Activity Relationship, Molecular Docking and Molecular Dynamics of imidazo[4,5-b] pyridine Derivatives as PDE Inhibitors

The Phosphodiesterase (PDE) enzymes adjust the intracellular signaling of cyclic adenosine 3′- 5′-monophosphate (cAMP) and cyclic guanosine 3′-5′-monophosphate (cGMP) by cleaving their phosphodiester bonds and converting them to AMP and GMP. Whereas 10 out of 11 PDE isoforms have splice variants in the CNS, it has been postulated that having the means to control the activity of a particular PDE isoform in the CNS could be helpful in a range of neuropsychiatric and neurodegenerative diseases such as psychosis, depression, Alzheimer’s disease, Parkinson s disease, etc. [1]. In this work, a three-dimensional quantitative structure-activity relationship(3D-QSAR) was used to establish models of 65 imidazo[4,5-b] pyridine derivatives to explore the quantitative structureactivity relationship as PDE inhibitors [2]. The effect of the docked conformer of each molecule in the enzyme cavity was investigated on the predictive ability and statistical quality of the produced models. Furthermore, a molecular dynamics simulation was applied to recognize end having better insight into the molecule’s Hype of molecular interactions. A few key residues (PHE719, GLN 716, SER 667, TRY 683) at the active site of PDE were identified.