Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease
<div><p>The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable du...
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2022
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| _version_ | 1864513519269969920 |
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| author | Balasubramanian Moovarkumudalvan (18300811) |
| author2 | Anupriya Madhukumar Geethakumari (18300814) Ramya Ramadoss (16003318) Kabir H. Biswas (5705864) Borbala Mifsud (3907267) |
| author2_role | author author author author |
| author_facet | Balasubramanian Moovarkumudalvan (18300811) Anupriya Madhukumar Geethakumari (18300814) Ramya Ramadoss (16003318) Kabir H. Biswas (5705864) Borbala Mifsud (3907267) |
| author_role | author |
| dc.creator.none.fl_str_mv | Balasubramanian Moovarkumudalvan (18300811) Anupriya Madhukumar Geethakumari (18300814) Ramya Ramadoss (16003318) Kabir H. Biswas (5705864) Borbala Mifsud (3907267) |
| dc.date.none.fl_str_mv | 2022-11-25T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/biom12121754 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Structure-Based_Virtual_Screening_and_Functional_Validation_of_Potential_Hit_Molecules_Targeting_the_SARS-CoV-2_Main_Protease/25539586 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology COVID-19 SARS-CoV-2 main protease structure-based virtual screening molecular docking FDA-approved drugs natural products deep learning BRET |
| dc.title.none.fl_str_mv | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><p>The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable due to challenges regarding production, logistics, distribution and vaccine hesitancy. Furthermore, vaccines are less effective against new variants of the SARS-CoV-2 virus and vaccination-induced immunity fades over time. These challenges and the vaccines’ ineffectiveness for the infected population necessitate improved treatment options, including the inhibition of the SARS-CoV-2 main protease (Mpro). Drug repurposing to achieve inhibition could provide an immediate solution for disease management. Here, we used structure-based virtual screening (SBVS) to identify natural products (from NP-lib) and FDA-approved drugs (from e-Drug3D-lib and Drugs-lib) which bind to the Mpro active site with high-affinity and therefore could be designated as potential inhibitors. We prioritized nine candidate inhibitors (e-Drug3D-lib: Ciclesonide, Losartan and Telmisartan; Drugs-lib: Flezelastine, Hesperidin and Niceverine; NP-lib: three natural products) and predicted their half maximum inhibitory concentration using DeepPurpose, a deep learning tool for drug–target interactions. Finally, we experimentally validated Losartan and two of the natural products as in vitro Mpro inhibitors, using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor. Our study suggests that existing drugs and natural products could be explored for the treatment of COVID-19.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Biomolecules<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/biom12121754" target="_blank">https://dx.doi.org/10.3390/biom12121754</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_06eaf838c979b05ec3991c54bae664da |
| identifier_str_mv | 10.3390/biom12121754 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25539586 |
| publishDate | 2022 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main ProteaseBalasubramanian Moovarkumudalvan (18300811)Anupriya Madhukumar Geethakumari (18300814)Ramya Ramadoss (16003318)Kabir H. Biswas (5705864)Borbala Mifsud (3907267)Biological sciencesBiochemistry and cell biologyCOVID-19SARS-CoV-2 main proteasestructure-based virtual screeningmolecular dockingFDA-approved drugsnatural productsdeep learningBRET<div><p>The recent global health emergency caused by the coronavirus disease 2019 (COVID-19) pandemic has taken a heavy toll, both in terms of lives and economies. Vaccines against the disease have been developed, but the efficiency of vaccination campaigns worldwide has been variable due to challenges regarding production, logistics, distribution and vaccine hesitancy. Furthermore, vaccines are less effective against new variants of the SARS-CoV-2 virus and vaccination-induced immunity fades over time. These challenges and the vaccines’ ineffectiveness for the infected population necessitate improved treatment options, including the inhibition of the SARS-CoV-2 main protease (Mpro). Drug repurposing to achieve inhibition could provide an immediate solution for disease management. Here, we used structure-based virtual screening (SBVS) to identify natural products (from NP-lib) and FDA-approved drugs (from e-Drug3D-lib and Drugs-lib) which bind to the Mpro active site with high-affinity and therefore could be designated as potential inhibitors. We prioritized nine candidate inhibitors (e-Drug3D-lib: Ciclesonide, Losartan and Telmisartan; Drugs-lib: Flezelastine, Hesperidin and Niceverine; NP-lib: three natural products) and predicted their half maximum inhibitory concentration using DeepPurpose, a deep learning tool for drug–target interactions. Finally, we experimentally validated Losartan and two of the natural products as in vitro Mpro inhibitors, using a bioluminescence resonance energy transfer (BRET)-based Mpro sensor. Our study suggests that existing drugs and natural products could be explored for the treatment of COVID-19.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Biomolecules<br> License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/biom12121754" target="_blank">https://dx.doi.org/10.3390/biom12121754</a></p>2022-11-25T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/biom12121754https://figshare.com/articles/journal_contribution/Structure-Based_Virtual_Screening_and_Functional_Validation_of_Potential_Hit_Molecules_Targeting_the_SARS-CoV-2_Main_Protease/25539586CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/255395862022-11-25T03:00:00Z |
| spellingShingle | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease Balasubramanian Moovarkumudalvan (18300811) Biological sciences Biochemistry and cell biology COVID-19 SARS-CoV-2 main protease structure-based virtual screening molecular docking FDA-approved drugs natural products deep learning BRET |
| status_str | publishedVersion |
| title | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease |
| title_full | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease |
| title_fullStr | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease |
| title_full_unstemmed | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease |
| title_short | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease |
| title_sort | Structure-Based Virtual Screening and Functional Validation of Potential Hit Molecules Targeting the SARS-CoV-2 Main Protease |
| topic | Biological sciences Biochemistry and cell biology COVID-19 SARS-CoV-2 main protease structure-based virtual screening molecular docking FDA-approved drugs natural products deep learning BRET |