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

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          Abstract

          We investigate binding of linoleate and other potential ligands to the recently discovered fatty acid binding site in the SARS‐CoV‐2 spike protein, using docking and molecular dynamics simulations. Simulations suggest that linoleate and dexamethasone stabilize the locked spike conformation, thus reducing the opportunity for ACE2 interaction. In contrast, cholesterol may expose the receptor‐binding domain by destabilizing the closed structure, preferentially binding to a different site in the hinge region of the open structure. We docked a library of FDA‐approved drugs to the fatty acid site using an approach that reproduces the structure of the linoleate complex. Docking identifies steroids (including dexamethasone and vitamin D); retinoids (some known to be active in vitro, and vitamin A); and vitamin K as potential ligands that may stabilize the closed conformation. The SARS‐CoV‐2 spike fatty acid site may bind a diverse array of ligands, including dietary components, and therefore provides a promising target for therapeutics or prophylaxis.

          Abstract

          Vitamin K2 docked at the fatty acid site in the closed SARS‐CoV‐2 spike protein. Simulations indicate that ligands binding at this site stabilize the closed spike conformation.

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          Author and article information

          Contributors
          Jim.Spencer@bristol.ac.uk
          Adrian.Mulholland@bristol.ac.uk
          Journal
          Angew Chem Int Ed Engl
          Angew Chem Int Ed Engl
          10.1002/(ISSN)1521-3773
          ANIE
          Angewandte Chemie (International Ed. in English)
          John Wiley and Sons Inc. (Hoboken )
          1433-7851
          1521-3773
          22 February 2021
          22 March 2021
          : 60
          : 13 ( doiID: 10.1002/anie.v60.13 )
          : 7098-7110
          Affiliations
          [ 1 ] School of Biochemistry University of Bristol 1 Tankard's Close Bristol BS8 1TD UK
          [ 2 ] Bristol Synthetic Biology Centre BrisSynBio 24 Tyndall Ave Bristol BS8 1TQ UK
          [ 3 ] School of Cellular and Molecular Medicine, Biomedical Sciences Building University of Bristol Bristol BS8 1TD UK
          [ 4 ] Max Planck Bristol Centre for Minimal Biology Cantock's Close Bristol BS8 1TS UK
          [ 5 ] School of Chemistry University of Bristol Bristol BS8 1TS UK
          Author notes
          [+]

          These authors contributed equally to this work.

          Author information
          http://orcid.org/0000-0002-1240-8463
          http://orcid.org/0000-0003-4125-4691
          http://orcid.org/0000-0001-9984-5940
          http://orcid.org/0000-0003-0320-0895
          http://orcid.org/0000-0002-1136-4008
          http://orcid.org/0000-0001-7518-9045
          http://orcid.org/0000-0002-1516-9760
          http://orcid.org/0000-0003-1015-4567
          Article
          ANIE202015639
          10.1002/anie.202015639
          8013358
          33469977
          eb95d559-a27e-4cad-98ea-40573ae22acd
          © 2021 Wiley‐VCH GmbH

          This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response. It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.

          History
          : 18 December 2020
          : 23 November 2020
          Page count
          Figures: 9, Tables: 0, References: 57, Pages: 13, Words: 0
          Funding
          Funded by: Biotechnology and Biological Sciences Research Council , open-funder-registry 10.13039/501100000268;
          Award ID: BB/L01386X/1
          Award ID: BB/P000940/1
          Funded by: British Society for Antimicrobial Chemotherapy , open-funder-registry 10.13039/501100000313;
          Award ID: BSAC-COVID-30
          Funded by: Engineering and Physical Sciences Research Council , open-funder-registry 10.13039/501100000266;
          Award ID: EP/M022609/1
          Funded by: Wellcome Trust , open-funder-registry 10.13039/100010269;
          Award ID: 210701/Z/18/Z
          Award ID: 106115/Z/14/Z
          Categories
          Research Article
          Research Articles
          Therapeutics | Hot Paper
          Custom metadata
          2.0
          March 22, 2021
          Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.1 mode:remove_FC converted:01.04.2021

          Chemistry
          molecular modeling,retinoids,sars-cov-2 spike fatty-acid-site,steroids,vitamins
          Chemistry
          molecular modeling, retinoids, sars-cov-2 spike fatty-acid-site, steroids, vitamins

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