Structures of ebolavirus glycoprotein complexes with tricyclic antidepressant and antipsychotic drugs

DOI: 10.1021/acs.jmedchem.8b00350

Authors: Yuguang Zhao (University of Oxford) , Jingshan Ren (University of Oxford) , Elizabeth E. Fry (University of Oxford) , Julia Xiao (University of Oxford) , Alain R. Townsend (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: May 2018
Diamond Proposal Number(s): 10627

Abstract: A large number of Food and Drug Administration (FDA) approved drugs have been found to inhibit cell entry of Ebola virus (EBOV). However, since these drugs have various primary pharmacological targets their mechanisms of action against EBOV remain largely unknown. We have previously shown that six FDA approved drugs inhibit EBOV infection by interacting with and destabilizing the viral glycoprotein (GP). Here we show that the antidepressants imipramine and clomipramine, and antipsychotic drug thioridazine also directly interact with EBOV GP, and determine the mode of interaction by crystallographic analysis of the complexes. The compounds bind within the same pocket as observed for other, chemically divergent, complexes but with different binding modes. These details should be of value for the development of potent EBOV inhibitors.

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

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