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Structure-based in silico screening identifies a potent ebolavirus inhibitor from a traditional Chinese medicine library

DOI: 10.1021/acs.jmedchem.8b01328 DOI Help

Authors: Faraz Shaikh (University of Macau; University of Oxford) , Yuguang Zhao (University of Oxford) , Luis Alvarez (University of Oxford) , Maria Iliopoulou (University of Oxford) , Christopher Thomas Lohans (University of Oxford) , Christopher J. Schofield (University of Oxford) , Sergi Padilla-Parra (University of Oxford; Ikerbasque, Basque Foundation for Science) , Shirley W. I. Siu (University of Macau) , Elizabeth Fry (University of Oxford) , Jingshan Ren (University of Oxford) , David I. Stuart (Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: February 2019
Diamond Proposal Number(s): 10627

Open Access Open Access

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 anti-viral compounds.

Journal Keywords: Infectious diseases; Assays; Inhibitors; Cavities; Molecules

Diamond Keywords: Ebola; Viruses

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 25/02/2019 09:51


Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Disease in the Developing World Drug Discovery Infectious Diseases Pathogens Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)