title: Discovery of Novel Phosphodiesterase-2A Inhibitors by Structure-Based Virtual Screening, Structural Optimization, and Bioassay.
abstract: Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer's disease and pulmonary hypertension. However, most of the current PDE2A inhibitors have moderate selectivity over other PDEs. In the present study, we described the discovery of novel PDE2A inhibitors by structure-based virtual screening combining pharmacophore model screening, molecular docking, molecular dynamics simulations, and bioassay validation. Nine hits out of 30 molecules from the SPECS database (a hit rate of 30%) inhibited PDE2A with affinity less than 50 μM. Optimization of compound AQ-390/10779040 (IC50= 4.6 μM) from the virtual screening, which holds a novel scaffold of benzo[cd]indol-2(1H)-one among PDE inhibitors, leads to discovery of a new compound LHB-8 with a significant improvement of inhibition (IC50= 570 nM). The modeling studies demonstrated that LHB-8 formed an extra hydrogen bond with Asp808 and a hydrophobic interaction with Thr768, in addition to the common interactions with Gln859 and Phe862 of PDE2A. The novel scaffolds discovered in the present study can be used for rational design of PDE2A inhibitors with high affinity.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou, 510006, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou, 510006, China.
authors.forename: Ling-Jun
authors.initials: LJ
authors.lastname: Feng
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou, 510006, China.
authors.forename: Yiyou
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou, 510006, China.
authors.forename: Deyan
authors.initials: D
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou, 510006, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou, 510006, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou, 510006, China.
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou, 510006, China.|Collaborative Innovation Center of High Performance Computing, National University of Defense Technology , Changsha 410073, China.
authors.forename: Hai-Bin
authors.identifier: 0000-0002-2163-0509
authors.initials: HB
authors.lastname: Luo
mesh_terms: D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006860:Hydrogen Bonding; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D014584:User-Computer Interface
chemical_list: D007211:Indoles; D010726:Phosphodiesterase Inhibitors; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2