Author(s): Chen, CY (Chen, Chien-yu); Chang, YH (Chang, Yea-huey); Bau, DT (Bau, Da- tian); Huang, HJ (Huang, Hung-jin); Tsai, FJ (Tsai, Fuu-jen); Tsai, CH (Tsai, Chang-hai);
Chen, CYC (Chen, Calvin Yu-chian)
Title: Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis
Source: ACTA PHARMACOLOGICA SINICA, 30 (8): 1186-1194 AUG 2009 Language: English
Document Type: Article
Author Keywords: phosphodiesterase5 (PDE5); Epimedium sagittatum; erectile dysfunction;
pharmacophore analysis; quantitative structure-activity; relationship
KeyWords Plus: PHARMACOINFORMATICS APPROACH; DERIVATIVES; SUANZAOREN;
PDE5; SILDENAFIL; RECEPTORS; LIGANDS; AGONIST; BINDING; ASSAY
Abstract: 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.
Addresses: [Tsai, Fuu-jen] China Med Univ Hosp, Dept Med Genet Pediat & Med Res, Taichung 40402, Taiwan; [Tsai, Fuu-jen] China Med Univ, Coll Chinese Med, Taichung 40402, Taiwan; [Chen, Chien-yu; Chang, Yea-huey; Bau, Da-tian; Huang, Hung-jin; Chen, Calvin Yu- chian] China Med Univ, Dept Biol Sci & Technol, Lab Pharmacoinformat & Nanotechnol, Taichung 40402, Taiwan; [Bau, Da-tian; Chen, Calvin Yu-chian] China Med Univ, Grad Inst Chinese Med Sci, Taichung 40402, Taiwan; [Bau, Da-tian; Chen, Calvin Yu-chian] China Med Univ Hosp, Terry Fox Canc Res Lab, Taichung 40402, Taiwan; [Tsai, Fuu-jen; Chen, Calvin Yu-chian] Asia Univ, Dept Bioinformat, Taichung 41354, Taiwan; [Tsai, Chang-hai] Asia Univ, Dept Healthcare Adm, Taichung 41354, Taiwan; [Chen, Calvin Yu-chian] MIT, Dept Biol Engn, Cambridge, MA 02139 USA; [Chen, Calvin Yu-chian] MIT, Ctr Canc Res, Cambridge, MA 02139 USA
Reprint Address: Tsai, FJ, China Med Univ Hosp, Dept Med Genet Pediat & Med Res, Taichung 40402, Taiwan.
E-mail Address: [email protected]; [email protected]; [email protected] Funding Acknowledgement:
Funding Agency Grant Number
National Science Council of China (NSC) 94-2213-E-039-002
China Medical University CMU97-CMC-014 CMU96-178
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.
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Publisher: NATURE PUBLISHING GROUP
Publisher Address: MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND ISSN: 1671-4083
DOI: 10.1038/aps.2009.100
29-char Source Abbrev.: ACTA PHARMACOL SIN ISO Source Abbrev.: Acta Pharmacol. Sin.
Source Item Page Count: 9
Subject Category: Chemistry, Multidisciplinary; Pharmacology & Pharmacy ISI Document Delivery No.: 484AU
