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Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection.
J Med Chem. 2018 02 08; 61(3):724-733.JM

Abstract

Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as reported for the anticancer drug toremifene and the painkiller ibuprofen, which bind in the same large cavity on the glycoprotein. Crystal structures show that the position of binding and the mode of interaction within the pocket vary significantly between these compounds. The binding constants (Kd) determined by thermal shift assay correlate with the protein-inhibitor interactions as well as with the antiviral activities determined by virus cell entry assays, supporting the hypothesis that these drugs inhibit viral entry by binding the glycoprotein and destabilizing the prefusion conformation. Details of the protein-inhibitor interactions of these complexes and their relation with binding affinity may facilitate the design of more potent inhibitors.

Authors+Show Affiliations

Division of Structural Biology, University of Oxford , The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, OX3 7BN, U.K.Division of Structural Biology, University of Oxford , The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, OX3 7BN, U.K.Division of Structural Biology, University of Oxford , The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, OX3 7BN, U.K.Division of Structural Biology, University of Oxford , The Henry Wellcome Building for Genomic Medicine, Headington, Oxford, OX3 7BN, U.K. Diamond Light Source Ltd. , Harwell Science & Innovation Campus, Didcot, OX11 0DE, U.K.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29272110

Citation

Ren, Jingshan, et al. "Target Identification and Mode of Action of Four Chemically Divergent Drugs Against Ebolavirus Infection." Journal of Medicinal Chemistry, vol. 61, no. 3, 2018, pp. 724-733.
Ren J, Zhao Y, Fry EE, et al. Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection. J Med Chem. 2018;61(3):724-733.
Ren, J., Zhao, Y., Fry, E. E., & Stuart, D. I. (2018). Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection. Journal of Medicinal Chemistry, 61(3), 724-733. https://doi.org/10.1021/acs.jmedchem.7b01249
Ren J, et al. Target Identification and Mode of Action of Four Chemically Divergent Drugs Against Ebolavirus Infection. J Med Chem. 2018 02 8;61(3):724-733. PubMed PMID: 29272110.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection. AU - Ren,Jingshan, AU - Zhao,Yuguang, AU - Fry,Elizabeth E, AU - Stuart,David I, Y1 - 2018/01/16/ PY - 2017/12/23/pubmed PY - 2019/2/26/medline PY - 2017/12/23/entrez SP - 724 EP - 733 JF - Journal of medicinal chemistry JO - J. Med. Chem. VL - 61 IS - 3 N2 - Here, we show that four chemically divergent approved drugs reported to inhibit Ebolavirus infection, benztropine, bepridil, paroxetine and sertraline, directly interact with the Ebolavirus glycoprotein. Binding of these drugs destabilizes the protein, suggesting that this may be the mechanism of inhibition, as reported for the anticancer drug toremifene and the painkiller ibuprofen, which bind in the same large cavity on the glycoprotein. Crystal structures show that the position of binding and the mode of interaction within the pocket vary significantly between these compounds. The binding constants (Kd) determined by thermal shift assay correlate with the protein-inhibitor interactions as well as with the antiviral activities determined by virus cell entry assays, supporting the hypothesis that these drugs inhibit viral entry by binding the glycoprotein and destabilizing the prefusion conformation. Details of the protein-inhibitor interactions of these complexes and their relation with binding affinity may facilitate the design of more potent inhibitors. SN - 1520-4804 UR - https://www.unboundmedicine.com/medline/citation/29272110/Target_Identification_and_Mode_of_Action_of_Four_Chemically_Divergent_Drugs_against_Ebolavirus_Infection L2 - https://dx.doi.org/10.1021/acs.jmedchem.7b01249 DB - PRIME DP - Unbound Medicine ER -