Acta Pharmacologica Sinica (2009) 30: 1186-1194; doi: 10.1038/aps.2009.100

Acta Pharmacologica Sinica (2009) 30: 1186-1194; doi: 10.1038/aps.2009.100; published online 13 July 2009

Original Article

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

Chien-yu Chen^1,#, Yea-huey CHANG^1,#, Da-tian BAU^1,2,3,#, Hung-jin HUANG¹, Fuu-jen Tsai^4,5,*, Chang-hai TSAI^6,*, Calvin Yu-chian Chen^1,2,3,5^,7,*

¹Laboratory of Pharmacoinformatics and Nanotechnology, Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan, China; ²Graduate Institute of Chinese Medical Science, China Medical University, Taichung 40402, Taiwan, China; ³Terry Fox Cancer Research Lab, China Medical University Hospital, Taichung 40402, Taiwan, China; ⁴Department of Medical Genetics, Pediatrics and Medical Research, China Medical University Hospital and College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan, China; ⁵Department of Bioinformatics, Asia University, Taichung 41354, Taiwan, China; ⁶Department of Healthcare Administration, Asia University, Taichung 41354, Taiwan, China; ⁷Department of Biological Engineering and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

Aim: To explore the potent inhibitor from one of the Traditional Chinese medicine (TCM), Epimedium sagittatum.

Methods: We predicted the potent compound, ES03b, 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: ES03b 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. ES03b 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.

Keywords: phosphodiesterase5 (PDE5); Epimedium sagittatum; erectile dysfunction; pharmacophore analysis; quantitative structure-activity relationship

The research was supported by grants from the National Science Council of China (NSC 94-2213-E-039-002) and China Medical University (CMU97-CMC-014, CMU96-178). We are grateful to the National Center for High-performance Computing for computer time and facilities.

^#These authors contributed equally to this work.
* To whom correspondence should be addressed.
Email ycc@mail.cmu.edu.tw; d0704@mail.cmuh.org.tw; chtsai@mail.cmu.edu.tw
Received 2009-04-14 Accepted 2009-05-15

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