Identify natural compounds as novel phosphodiesterase-2A inhibitors.

Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for the treatment of ganglion dysfunction-related diseases such as Alzheimer's disease, schizophrenia, cognitive impairment, anxiety, and depression. However, most current PDE2A inhibitors have moderate selectivity compared to other PDEs. In this study, we described the discovery of 6 novel PDE2A inhibitors by bioassays, molecular docking, and molecular dynamics simulations. Six molecules out of 2592 compounds from the L6000-Natural Compound Library inhibited PDE2A with affinity ranging from 4.03 to 39.84 μM. Selective experiments were carried out on PDE4D, PDE5A, PDE9A, and PDE10A, among which 5-5H and 16-2H exhibited good dual inhibition against both PDE2A and PDE4D. Their IC₅₀ values for PDE2A were 4.03 and 9.08 μM, respectively, and for PDE4D they were 3.89 and 10.96 μM, respectively. Molecular docking and molecular dynamics simulation were used to explore the binding modes of active compounds with PDE2A. It is shown that in addition to the common interactions with Gln859 and Phe862 of PDE2A, 6 molecules formed extra hydrogen bonds with Ile826 and Leu809. These molecules may serve as starting points for further optimization of selective PDE2A inhibitors.