Structure-Based in Silico Screening Identifies a Potent Ebolavirus Inhibitor from a Traditional Chinese Medicine Library.

Journal of Medicinal Chemistry
Faraz ShaikhDavid I Stuart

Abstract

Potent 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 IC50 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.

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Citations

Feb 10, 2021·Trends in Food Science & Technology·Rohit ThirumdasFrancisco J Barba
Sep 6, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Muhammad Usman MirzaMatheus Froeyen
Apr 18, 2021·Journal of Molecular Modeling·Debarati PaulShubhra Ghosh Dastidar
Aug 25, 2020·ACS Medicinal Chemistry Letters·Thomas R Lane, Sean Ekins
Jun 23, 2020·ACS Infectious Diseases·Minetaro AritaNobuo Kawahara
Jun 20, 2020·ACS Medicinal Chemistry Letters·Michael B PleweKen McCormack

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Methods Mentioned

BETA
X-ray
thermal shift
Thermal
Assay
NMR
transfection
size exclusion chromatography

Software Mentioned

QPLD
Schrödinger
CNS
Cellsens
Maestro
ImageJ
REFMAC5
Xia2
VOLUMES
Icy

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