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


CONCLUSIONS
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.
Chen
Chien-yu
CY
Laboratory of Pharmacoinformatics and Nanotechnology, Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan, China.
Chang
Yea-huey
YH
Bau
Da-tian
DT
Huang
Hung-jin
HJ
Tsai
Fuu-jen
FJ
Tsai
Chang-hai
CH
Chen
Calvin Yu-chian
CY
D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000378:metabolism*; D004365:Drugs, Chinese Herbal / Q000737:chemistry* / Q000494:pharmacology*; D034181:Epimedium / Q000737:chemistry*; D007172:Erectile Dysfunction / Q000188:drug therapy; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship
D004365:Drugs, Chinese Herbal; D058986:Phosphodiesterase 5 Inhibitors; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5