title: Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping.
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.
authors: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
authors: Jing
authors: J
authors: Deng
authors: Ning
authors: N
authors: Li
authors: Hongchuan
authors: H
authors: Liu
authors: Zhili
authors: Z
authors: Zuo
authors: Oi Wah
authors: OW
authors: Liew
authors: Weijun
authors: W
authors: Xu
authors: Gang
authors: G
authors: Chen
authors: Xiankun
authors: X
authors: Tong
authors: Wei
authors: W
authors: Tang
authors: Jin
authors: J
authors: Zhu
authors: Jianping
authors: J
authors: Zuo
authors: Hualiang
authors: H
authors: Jiang
authors: Cai-Guang
authors: CG
authors: Yang
authors: Jian
authors: J
authors: Li
authors: Weiliang
authors: W
authors: Zhu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014584:User-Computer Interface; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014779:Virus Replication / Q000187:drug effects; D000085242:Viral Proteases
chemical_list: D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases