jm7b01249_si_001.csv (0.27 kB)
Target Identification and Mode of Action of Four Chemically Divergent Drugs against Ebolavirus Infection
dataset
posted on 2017-12-22, 00:00 authored by Jingshan Ren, Yuguang Zhao, Elizabeth E. Fry, David I. StuartHere, 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.