Identification of lead BAY60-7550 analogues as potential inhibitors that utilize the hydrophobic groove in PDE2A: a molecular dynamics simulation study

The phosphodiesterase (PDE) family of proteins are important regulators of signal transduction, which they achieve by controlling the secondary messengers cyclic AMP (cAMP) and cyclic GMP (cGMP). cAMP and cGMP are involved in many critical intracellular processes such as gene transcription, kinase activation, signal transduction in learning and memory, and channel function as secondary messengers. The involvement of PDEs in neuronal communication has made them important therapeutic targets. Considering the recent discovery that PDE2A inhibition can improve cognitive functioning, a combined molecular dynamics simulation and scoring and docking study was carried out to identify selective inhibitors of PDE2A that specifically interact with the recently discovered hydrophobic groove in PDE2A. Using the X-ray crystal structure of PDE2A (from PDB ID: 4HTX), we investigated the binding modes of a range of promising inhibitors based on the known PDE2A inhibitor BAY60-7550 to PDE2A. Graphical abstract The lead molecule showing highest MMPBSA binding energy with 2D and 3D binding pose in hydrophobic groove.