In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket

Queirós-Reis, Luís; Kaarbo̷, Mari; Al-Baldawi, Huda; Alvites, Rui; Maurício, Ana Colette; Brancale, Andrea; Bassetto, Marcella; Mesquita, João R

doi:10.1021/acsomega.4c10519

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In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket

Luís Queirós-Reis

, Mari Kaarbo̷, Huda Al-Baldawi, Rui Alvites, Ana Colette Maurício, Andrea Brancale

, Marcella Bassetto, João R Mesquita

ACS Omega, Volume: 10, Issue: 23, Pages: 24117 - 24132

Swansea University Author: Marcella Bassetto

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DOI (Published version): 10.1021/acsomega.4c10519

Abstract

The key viral protein for infection by SARS-CoV-2 is the spike glycoprotein (S protein), mediating entry into host cells, which therefore represents a strong focus for the development of targeted therapeutics. In this work, we explored the fatty acid binding pocket within the S protein, which stabil...

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Published in:	ACS Omega
ISSN:	2470-1343
Published:	American Chemical Society (ACS) 2025
Online Access:	Check full text
URI:	https://cronfa.swan.ac.uk/Record/cronfa69863

first_indexed	2025-07-02T09:12:29Z
last_indexed	2025-07-04T03:55:51Z
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To explore the potential of this site as a drug target, molecular dynamics simulations were performed, followed by a docking-based virtual screening of commercial druglike compounds. This in silico procedure enabled the identification of potential inhibitors of SARS-CoV-2 cell infection, likely by stabilizing an inactive spike conformation, detected in binding assays, although further experiments are required to directly confirm this action. The antiviral effect of the virtual hits was analyzed in cell-based assays, and one molecule displayed a low micromolar activity. Starting from the best antiviral compound found, structural analogues were purchased and evaluated in antiviral assays. An increase in activity was observed for multiple analogues, with the strongest antiviral compound showing submicromolar activity and low cytotoxicity. The successful identification of a new antiviral scaffold through in silico studies might pave the way for the further development of antivirals against SARS-CoV-2 and shows the reliability of the methodologies applied.</abstract><type>Journal Article</type><journal>ACS Omega</journal><volume>10</volume><journalNumber>23</journalNumber><paginationStart>24117</paginationStart><paginationEnd>24132</paginationEnd><publisher>American Chemical Society (ACS)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2470-1343</issnElectronic><keywords/><publishedDay>17</publishedDay><publishedMonth>6</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-06-17</publishedDate><doi>10.1021/acsomega.4c10519</doi><url/><notes/><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>L.Q.-R. would like to acknowledge Fundação para a Ciência e para a Tecnologia for the grant “2020.10230.BD” under the program “DOCTORATES 4 COVID-19” and EEA Grants/Norway Grants for the grant “FBR_OC52_53”. R.A. acknowledges the Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA), Porto University (UP), and Fundação para a Ciência e Tecnologia (FCT) for the funding and availability of all technical, structural, and human resources necessary for the development of this work. 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spelling	2025-07-02T10:14:18.1813494 v2 69863 2025-07-02 In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false 2025-07-02 The key viral protein for infection by SARS-CoV-2 is the spike glycoprotein (S protein), mediating entry into host cells, which therefore represents a strong focus for the development of targeted therapeutics. In this work, we explored the fatty acid binding pocket within the S protein, which stabilizes an inactive conformation and disrupts cell recognition and infection. To explore the potential of this site as a drug target, molecular dynamics simulations were performed, followed by a docking-based virtual screening of commercial druglike compounds. This in silico procedure enabled the identification of potential inhibitors of SARS-CoV-2 cell infection, likely by stabilizing an inactive spike conformation, detected in binding assays, although further experiments are required to directly confirm this action. The antiviral effect of the virtual hits was analyzed in cell-based assays, and one molecule displayed a low micromolar activity. Starting from the best antiviral compound found, structural analogues were purchased and evaluated in antiviral assays. An increase in activity was observed for multiple analogues, with the strongest antiviral compound showing submicromolar activity and low cytotoxicity. The successful identification of a new antiviral scaffold through in silico studies might pave the way for the further development of antivirals against SARS-CoV-2 and shows the reliability of the methodologies applied. Journal Article ACS Omega 10 23 24117 24132 American Chemical Society (ACS) 2470-1343 17 6 2025 2025-06-17 10.1021/acsomega.4c10519 COLLEGE NANME COLLEGE CODE Swansea University Another institution paid the OA fee L.Q.-R. would like to acknowledge Fundação para a Ciência e para a Tecnologia for the grant “2020.10230.BD” under the program “DOCTORATES 4 COVID-19” and EEA Grants/Norway Grants for the grant “FBR_OC52_53”. R.A. acknowledges the Centro de Estudos de Ciência Animal (CECA), Instituto de Ciências, Tecnologias e Agroambiente (ICETA), Porto University (UP), and Fundação para a Ciência e Tecnologia (FCT) for the funding and availability of all technical, structural, and human resources necessary for the development of this work. His participation in this project was supported through project UIDB/00211/2020 merged by FCT/MCTES through national funds and through project 2022.04501.PTDC (Olfabionerve─Olfactory Mucosa Mesenchymal StemCells and Biomaterials Promoting Peripheral Nerve Regeneration). 2025-07-02T10:14:18.1813494 2025-07-02T09:49:55.5598053 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Luís Queirós-Reis 0000-0002-5204-5046 1 Mari Kaarbo̷ 2 Huda Al-Baldawi 3 Rui Alvites 4 Ana Colette Maurício 5 Andrea Brancale 0000-0002-9728-3419 6 Marcella Bassetto 7 João R Mesquita 0000-0001-8769-8103 8 69863__34641__ef03458cdc1045e5ab308328c9ef4244.pdf 69863.VOR.pdf 2025-07-02T10:10:36.6711480 Output 11165245 application/pdf Version of Record true © 2025 The Authors. This article is licensed under CC-BY 4.0. true eng https://creativecommons.org/licenses/by/4.0/
title	In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket
spellingShingle	In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket Marcella Bassetto
title_short	In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket
title_full	In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket
title_fullStr	In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket
title_full_unstemmed	In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket
title_sort	In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket
author_id_str_mv	b97beeed16f8e0524551233ade909565
author_id_fullname_str_mv	b97beeed16f8e0524551233ade909565_***_Marcella Bassetto
author	Marcella Bassetto
author2	Luís Queirós-Reis Mari Kaarbo̷ Huda Al-Baldawi Rui Alvites Ana Colette Maurício Andrea Brancale Marcella Bassetto João R Mesquita
format	Journal article
container_title	ACS Omega
container_volume	10
container_issue	23
container_start_page	24117
publishDate	2025
institution	Swansea University
issn	2470-1343
doi_str_mv	10.1021/acsomega.4c10519
publisher	American Chemical Society (ACS)
college_str	Faculty of Science and Engineering
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hierarchy_top_id	facultyofscienceandengineering
hierarchy_top_title	Faculty of Science and Engineering
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department_str	School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
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description	The key viral protein for infection by SARS-CoV-2 is the spike glycoprotein (S protein), mediating entry into host cells, which therefore represents a strong focus for the development of targeted therapeutics. In this work, we explored the fatty acid binding pocket within the S protein, which stabilizes an inactive conformation and disrupts cell recognition and infection. To explore the potential of this site as a drug target, molecular dynamics simulations were performed, followed by a docking-based virtual screening of commercial druglike compounds. This in silico procedure enabled the identification of potential inhibitors of SARS-CoV-2 cell infection, likely by stabilizing an inactive spike conformation, detected in binding assays, although further experiments are required to directly confirm this action. The antiviral effect of the virtual hits was analyzed in cell-based assays, and one molecule displayed a low micromolar activity. Starting from the best antiviral compound found, structural analogues were purchased and evaluated in antiviral assays. An increase in activity was observed for multiple analogues, with the strongest antiviral compound showing submicromolar activity and low cytotoxicity. The successful identification of a new antiviral scaffold through in silico studies might pave the way for the further development of antivirals against SARS-CoV-2 and shows the reliability of the methodologies applied.
published_date	2025-06-17T05:29:18Z
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score	11.089407

In Silico Discovery of a Novel Antiviral Scaffold for SARS-CoV‑2 Targeting the Spike Glycoprotein through the Fatty Acid Binding Pocket

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