Computational determination of binding structures and free energies of phosphodiesterase-2 with benzo[1,4]diazepin-2-one derivatives.

Phosphodiesterase-2 (PDE2) is a key enzyme catalyzing hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that serve as intracellular second messengers. PDE2 has been recognized as an attractive drug target, and selective inhibitors of PDE2 are expected to be promising candidates for the memory enhancer, antidepressant, and anxiolytic agent. In the present study, we examined the detailed binding structures and free energies for PDE2 interacting with a promising series of inhibitors, i.e., benzo[1,4]diazepin-2-one derivatives, by carrying out molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decompositions. The computational results provide valuable insights into the detailed enzyme-inhibitor binding modes including important intermolecular interactions, e.g., the π-π stacking interactions with the common benzo[1,4]diazepin-2-one scaffold of the inhibitors, hydrogen bonding and hydrophobic interactions with the substituents on the benzo[1,4]diazepin-2-one scaffold. Future rational design of new, more potent inhibitors of PDE2 should carefully account for all of these favorable intermolecular interactions. By use of the MD-simulated binding structures, the calculated binding free energies are in good agreement with the experimental activity data for all of the examined benzo[1,4]diazepin-2-one derivatives. The enzyme-inhibitor binding modes determined and the agreement between the calculated and experimental results are expected to be valuable for future rational design of more potent inhibitors of PDE2.