Although an X-ray crystal structure of the catalytic domain of human cyclic nucleotide phosphodiesterase-2 (PDE2A) was reported in the literature, the shape of the binding pocket is not suitable for binding with its known potent inhibitors. Extensive molecular modeling, docking, and dynamics simulations in the present study have demonstrated for the first time that the structure of PDE2A catalytic domain may exist in two different forms corresponding to the inhibitor-bound and unbound states of the enzyme. The structural change from the unbound state to the bound state leads to a substantial variation in the size of the pocket but does not affect the general structural feature of the catalytic site. The flexible binding pocket and conserved structural feature of the catalytic site lead us to better understand why this enzyme can catalyze hydrolysis of two different intercellular second messengers. It has been demonstrated that the available X-ray crystal structure of PDE2A was in the unbound state, explaining why it is not Suitable for molecular docking studies on the enzyme-inhibitor binding. We have developed a reasonable 31) model of the PDE2A structure in the bound state and determined the detailed binding modes and binding free energies for PDE2A binding with its known potent inhibitors. The calculated binding free energies are in good agreement with available experimental data. The general structural insights, PDE2A model in the bound state, and detailed PDE2A-inhibitor binding structures obtained in this study will be valuable for future rational design of novel, potent inhibitors of PDE2A as therapeutic agents.