ChemRxiv
These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
1/1
4 files

Molecular Simulations suggest Vitamins, Retinoids and Steroids as Ligands binding the Free Fatty Acid Pocket of SARS-CoV-2 Spike Protein

preprint
submitted on 26.10.2020, 19:07 and posted on 28.10.2020, 10:13 by Deborah Shoemark, Charlotte Colenso, Christine Toelzer, Kapil Gupta, Richard Sessions, Andrew Davidson, Imre Berger, Christiane Schaffitzel, James Spencer, Adrian Mulholland

Following our recent identification of a fatty acid binding site in the SARS-CoV-2 spike protein (Toelzer et al., Science eabd3255 (2020)), we investigate the binding of linoleate and other potential ligands at this site using molecular dynamics simulations. The results support the hypothesis that linoleate stabilises the locked form of the spike, in which its interaction interface for the ACE2 receptor is occluded. The simulations indicate weaker binding of linoleate to the partially open conformation. Simulations of dexamethasone bound at this site indicate that it binds similarly to linoleate, and thus may also stabilize a locked spike conformation. In contrast, simulations suggest that cholesterol bound at this site may destabilize the locked conformation, and in the open conformation, may preferentially bind at an alternative site in the hinge region between the receptor binding domain and the domain below, which could have functional relevance. We also use molecular docking to identify potential ligands that may bind at the fatty acid binding site, using the Bristol University Docking Engine (BUDE). BUDE docking successfully reproduces the linoleate complex and also supports binding of dexamethasone at the spike fatty acid site. Virtual screening of a library of approved drugs identifies vitamins D, K and A, as well as retinoid ligands with experimentally demonstrated activity against SARS-CoV-2 replication in vitro, as also potentially able to bind at this site. Our data suggest that the fatty acid binding site of the SARS-CoV-2 spike protein may bind a diverse array of candidate ligands. Targeting this site with small molecules, including dietary components such as vitamins, which may stabilise its locked conformation and represents a potential avenue for novel therapeutics or prophylaxis for COVID-19.

Funding

BrisSynBio: Bristol Centre for Synthetic Biology

Biotechnology and Biological Sciences Research Council

Find out more...

CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface

Engineering and Physical Sciences Research Council

Find out more...

Structure and Mechanism of Key Nonsense-Mediated mRNA Decay Factor Complexes

Wellcome Trust

Find out more...

Unlocking the structure, mechanism and cellular assembly of key multiprotein complexes in human gene transcription.

Wellcome Trust

Find out more...

Membrane protein insertion and quality control by the bacterial holo-translocon and FtsH chaperone/protease complex

Biotechnology and Biological Sciences Research Council

Find out more...

History

Email Address of Submitting Author

deb.shoemark@bristol.ac.uk

Institution

University of Bristol

Country

United Kingdom

ORCID For Submitting Author

0000-0002-1240-8463

Declaration of Conflict of Interest

None

Version Notes

This is the first version uploaded to chemRxiv

Exports