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Title: Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping
Authors: Deng, J.
Li, N.
Liu, H.
Zuo, Z.
Liew, O.W. 
Xu, W.
Chen, G.
Tong, X.
Tang, W.
Zhu, J.
Zuo, J.
Jiang, H.
Yang, C.-G.
Li, J.
Zhu, W.
Issue Date: 26-Jul-2012
Citation: Deng, J., Li, N., Liu, H., Zuo, Z., Liew, O.W., Xu, W., Chen, G., Tong, X., Tang, W., Zhu, J., Zuo, J., Jiang, H., Yang, C.-G., Li, J., Zhu, W. (2012-07-26). Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping. Journal of Medicinal Chemistry 55 (14) : 6278-6293. ScholarBank@NUS Repository.
Abstract: By virtual screening, compound 1 was found to be active against NS2B-NS3 protease (IC 50 = 13.12 ± 1.03 μM). Fourteen derivatives (22) of compound 1 were synthesized, leading to the discovery of four new inhibitors with biological activity. In order to expand the chemical diversity of the inhibitors, small-molecule-based scaffold hopping was performed on the basis of the common scaffold of compounds 1 and 22. Twenty-one new compounds (23, 24) containing quinoline (new scaffold) were designed and synthesized. Protease inhibition assays revealed that 12 compounds with the new scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new compounds were discovered as NS2B-NS3 protease inhibitors with IC 50 values of 7.46 ± 1.15 to 48.59 ± 3.46 μM, and 8 compounds belonging to two different scaffolds are active to some extent against DENV based on luciferase reporter replicon-based assays. These novel chemical entities could serve as lead structures for discovering therapies against DENV. © 2012 American Chemical Society.
Source Title: Journal of Medicinal Chemistry
ISSN: 00222623
DOI: 10.1021/jm300146f
Appears in Collections:Staff Publications

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