Ezgimen, ManolyaLai, HuiguoMueller, Niklaus H.Lee, KyungaeCuny, Gregory D.Ostrov, David A.Padmanabhan, Radhakrishnan2020-03-102020-03-102013-04Copyright 2012 Antiviral Research. This is a post-print version of a published paper that is available at: https://www.sciencedirect.com/science/article/pii/S0166354212000368. Recommended citation: Ezgimen, Manolya, Huiguo Lai, Niklaus H. Mueller, Kyungae Lee, Gregory Cuny, David A. Ostrov, and Radhakrishnan Padmanabhan. "Characterization of the 8-hydroxyquinoline scaffold for inhibitors of West Nile virus serine protease." Antiviral research 94, no. 1 (2012): 18-24. doi: 10.1016/j.antiviral.2012.02.003. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.https://hdl.handle.net/10657/5951West Nile virus (WNV) is a mosquito-borne member of flaviviruses that causes significant morbidity and mortality especially among children. There is currently no approved vaccine or antiviral therapeutic for human use. In a previous study, we described compounds containing the 8-hydroxyquinoline (8-HQ) scaffold as inhibitors of WNV serine protease (NS2B/NS3pro) in a high throughput screen (HTS) using the purified WNV NS2B/NS3pro as the target. In this study, we analyzed potencies of some commercially available as well as chemically synthesized derivatives of 8-HQ by biochemical assays. An insight into the contribution of various substitutions of 8-HQ moiety for inhibition of the protease activity was revealed. Most importantly, the substitution of the N1 of the 8-HQ ring by –CH– in compound 26 significantly reduced the inhibition of the viral protease by this naphthalen-1-ol derivative. The kinetic constant (Ki) for the most potent 8-HQ inhibitor (compound 14) with an IC50 value of 2.01 ± 0.08 ?M using the tetra-peptide substrate was determined to be 5.8 ?M. This compound inhibits the WNV NS2B/NS3pro by a competitive mode of inhibition which is supported by molecular modeling.en-USWest Nile Virus protease inhibitorsMolecular modeling and dockingcompetitive inhibitors of West Nile vrius proteaseStructure activity relationship study among 8 hydroxyquinoline derivativesArticle