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Structure-Based in Silico Screening Identifies a Potent Ebolavirus Inhibitor from a Traditional Chinese Medicine Library
Shaikh F.4; Zhao Y.1; Alvarez L.1; Iliopoulou M.1; Lohans C.1; Schofield C.J.1; Padilla-Parra S.1; Siu S.W.I.4; Fry E.E.1; Ren J.1; Stuart D.I.1
2019-03-28
Source PublicationJournal of Medicinal Chemistry
ISSN15204804 00222623
Volume62Issue:6Pages:2928-2937
AbstractPotent Ebolavirus (EBOV) inhibitors will help to curtail outbreaks such as that which occurred in 2014-16 in West Africa. EBOV has on its surface a single glycoprotein (GP) critical for viral entry and membrane fusion. Recent high-resolution complexes of EBOV GP with a variety of approved drugs revealed that binding to a common cavity prevented fusion of the virus and endosomal membranes, inhibiting virus infection. We performed docking experiments, screening a database of natural compounds to identify those likely to bind at this site. Using both inhibition assays of HIV-1-derived pseudovirus cell entry and structural analyses of the complexes of the compounds with GP, we show here that two of these compounds attach in the common binding cavity, out of eight tested. In both cases, two molecules bind in the cavity. The two compounds are chemically similar, but the tighter binder has an additional chlorine atom that forms good halogen bonds to the protein and achieves an IC of 50 nM, making it the most potent GP-binding EBOV inhibitor yet identified, validating our screening approach for the discovery of novel antiviral compounds.
DOI10.1021/acs.jmedchem.8b01328
URLView the original
Language英語
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Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.University of Oxford
2.Diamond Light Source
3.Ikerbasque, the Basque Foundation for Science
4.Universidade de Macau
Recommended Citation
GB/T 7714
Shaikh F.,Zhao Y.,Alvarez L.,et al. Structure-Based in Silico Screening Identifies a Potent Ebolavirus Inhibitor from a Traditional Chinese Medicine Library[J]. Journal of Medicinal Chemistry,2019,62(6):2928-2937.
APA Shaikh F..,Zhao Y..,Alvarez L..,Iliopoulou M..,Lohans C..,...&Stuart D.I..(2019).Structure-Based in Silico Screening Identifies a Potent Ebolavirus Inhibitor from a Traditional Chinese Medicine Library.Journal of Medicinal Chemistry,62(6),2928-2937.
MLA Shaikh F.,et al."Structure-Based in Silico Screening Identifies a Potent Ebolavirus Inhibitor from a Traditional Chinese Medicine Library".Journal of Medicinal Chemistry 62.6(2019):2928-2937.
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