期刊
JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 57, 期 2, 页码 355-364出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.6b00551
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资金
- Natural Science Foundation of China [81522041, 21572279, 81373258, 21402243]
- Guangdong Science Foundation [2014A020210009]
- Science Foundation of Guangzhou City [2014J4100165]
- Research Fund for the Doctoral Program of Higher Education of China [20130171110096]
- Fundamental Research Funds for the Central Universities (Sun Yat-Sen University) [13ykpy10]
- Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme
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 Optimization of compound AQ-390/10779040 (IC50 = 4.6 mu M) 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.
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