Mechanistic insights into the identification of Phosphodiesterase 2 inhibitors from acridine analogues

Phosphodiesterase 2 (PDE2) has been relatively overlooked in CNS drug discovery despite its significant role in neuronal signaling, learning, memory, and emotion regulation. Therefore, the study was conducted to explore the potential of acridine analogues as PDE2a inhibitors through molecular docking, dynamics simulations, and binding free energy calculations. Molecular docking of acridine analogues with PDE2a revealed favorable binding conformations and interaction energies comparable to co-crystal ligands. Detailed interaction analysis highlighted key residues, such as Leu-809, Leu-770, and Ile-866, that had interacted with the hit molecules, which might contribute to subtype selectivity. Molecular dynamics (MD) simulations confirmed the structural stability of the hit molecules, with amsacrine demonstrating the most stable complex formation. Pulling simulations evaluated the binding affinities, showing that quinacrine and amsacrine required higher rupture forces than the two co-crystal ligands, indicating strong binding interactions. Binding free energy calculations using umbrella sampling further supported the strong affinities of the hit molecules, with amsacrine and quinacrine exhibiting the lowest binding free energies of −45.041 kcal/mol and −45.237 kcal/mol, respectively, indicating highly stable interactions with PDE2a. Moreover, Absolute binding free energy calculations using the MBAR method also suggested the favorable binding for the amsacrine followed by quinacrine, with values of −11.23 kcal/mol and −4.99 kcal/mol, respectively. This study revealed acridine analogues, particularly amsacrine and quinacrine, as promising PDE2a inhibitors, providing a foundation for further experimental validation and therapeutic development targeting CNS disorders.