Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis

• Published in: Acta pharmacologica Sinica 2009-08, Vol.30 (8), p.1186-1194
• Main Authors: Chen, Chien-yu, Chang, Yea-huey, Bau, Da-tian, Huang, Hung-jin, Tsai, Fuu-jen, Tsai, Chang-hai, Chen, Calvin Yu-chian
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacology; Epimedium - chemistry; Erectile Dysfunction - drug therapy; Humans; Immunology; Internal Medicine; Male; Medical Microbiology; Models, Molecular; Molecular Structure; Original; original-article; Pharmacology/Toxicology; Phosphodiesterase 5 Inhibitors; Protein Binding; Quantitative Structure-Activity Relationship; Vaccine; 传统中药; 分子对接; 多元线性回归; 抑制剂; 磷酸二酯酶; 结合位点; 药效分析; 虚拟筛选
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2009.100

Aim： To explore the potent inhibitor from one of the Traditional Chinese medicine （TCM）, Epimedium sagittatum. Methods： We predicted the potent compound, ESO3b, de novo evolution from the four Epimedium sagittatum components were verified by molecular docking, pharmacophore analysis, and analysis of quantitative structure-activity relationship （QSAR） model, which was constructed by multiple linear regression. Results： ESO3b was chosen to undergo drug modification via de novo evolution. By analyzing the pharmacophore features, we found that the hydrophobic core in the binding site and the hydrogen bond generated at Asn663 played key roles in designing PDE5 inhibitors. ESO3b generated 49 diversities （Evo01-49）. Evo48 had high activity in prediction. Although the value of prediction was overestimated, Evo48 was suggested as the potent lead. Conclusion： In this study, we showed that the hydrophobic core in the binding site and hydrogen bond production on Asn663 played key roles to design PDE5 inhibitors. From several require validation analysis, Evo48 was suggested to be a potent inhibitor.