Discovery of Novel Phosphodiesterase-2A Inhibitors by Structure-Based Virtual Screening, Structural Optimization, and Bioassay

• DOI: 10.1021/acs.jcim.6b00551
• Publication Date: 2017-01-05T21:00:11Z
• Authors: Chen Zhang; Ling-Jun Feng; Yiyou Huang; Deyan Wu; Zhe Li; Qian Zhou; Yinuo Wu; Hai-Bin Luo
• Keywords: Docking (animal); High-Throughput Screening; IC50

Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer's disease and pulmonary hypertension. However, most the current PDE2A inhibitors have moderate selectivity over other PDEs. In present study, we described discovery novel by structure-based virtual screening combining pharmacophore model screening, molecular docking, dynamics simulations, bioassay validation. Nine hits out 30 molecules from SPECS database (a hit rate 30%) inhibited with affinity less than 50 μM. Optimization compound AQ-390/10779040 (IC50 = 4.6 μM) which holds scaffold benzo[cd]indol-2(1H)-one among PDE inhibitors, leads to new LHB-8 significant improvement inhibition 570 nM). The modeling studies demonstrated that formed an extra hydrogen bond Asp808 hydrophobic interaction Thr768, in addition common interactions Gln859 Phe862 PDE2A. scaffolds discovered study can be used rational design high affinity.