The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses
Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (−...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Online Access: | https://www.mdpi.com/1999-4915/16/2/215 |
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| author | Olga I. Yarovaya Aleksandr S. Filimonov Dmitriy S. Baev Sophia S. Borisevich Anna V. Zaykovskaya Varvara Yu. Chirkova Mariya K. Marenina Yulia V. Meshkova Svetlana V. Belenkaya Dmitriy N. Shcherbakov Maxim A. Gureev Olga A. Luzina Oleg V. Pyankov Nariman F. Salakhutdinov Mikhail V. Khvostov |
| author_facet | Olga I. Yarovaya Aleksandr S. Filimonov Dmitriy S. Baev Sophia S. Borisevich Anna V. Zaykovskaya Varvara Yu. Chirkova Mariya K. Marenina Yulia V. Meshkova Svetlana V. Belenkaya Dmitriy N. Shcherbakov Maxim A. Gureev Olga A. Luzina Oleg V. Pyankov Nariman F. Salakhutdinov Mikhail V. Khvostov |
| author_sort | Olga I. Yarovaya |
| collection | DOAJ |
| description | Although the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (−)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed moderate activity. Derivatives containing nitro substituents in the thiophene heterocycle—just as pure (+)- and (−)-usnic acids—showed no anti-3CL<sup>pro</sup> activity. Kinetic parameters of the most active compound, <b>(+)-3e</b>, were investigated, and molecular modeling of the possible interaction of the new thiazolo-thiophenes with the active site of the main protease was carried out. We evaluated the binding energies of the ligand and protein in a ligand–protein complex. Active compound <b>(+)-3e</b> was found to bind with minimum free energy; the binding of inactive compound <b>(+)-3g</b> is characterized by higher values of minimum free energy; the positioning of pure (+)-usnic acid proved to be unstable and is accompanied by the formation of intermolecular contacts with many amino acids of the catalytic binding site. Thus, the molecular dynamics results were consistent with the experimental data. In an in vitro antiviral assay against six strains (Wuhan, Delta, and four Omicron sublineages) of SARS-CoV-2, <b>(+)-3e</b> demonstrated pronounced antiviral activity against all the strains. |
| first_indexed | 2024-03-07T22:11:37Z |
| format | Article |
| id | doaj.art-f8027d82e2904b38a99ec1ab28d8aae6 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-07T22:11:37Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-f8027d82e2904b38a99ec1ab28d8aae62024-02-23T15:37:31ZengMDPI AGViruses1999-49152024-01-0116221510.3390/v16020215The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 VirusesOlga I. Yarovaya0Aleksandr S. Filimonov1Dmitriy S. Baev2Sophia S. Borisevich3Anna V. Zaykovskaya4Varvara Yu. Chirkova5Mariya K. Marenina6Yulia V. Meshkova7Svetlana V. Belenkaya8Dmitriy N. Shcherbakov9Maxim A. Gureev10Olga A. Luzina11Oleg V. Pyankov12Nariman F. Salakhutdinov13Mikhail V. Khvostov14Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaSynchrotron Radiation Facility SKIF, G.K. Boreskov Institute of Catalysis SB RAS, 630559 Koltsovo, RussiaState Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, RussiaInstitute of Biology and Biotechnology, Altay State University, 656049 Barnaul, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaLaboratory of Bio- and Cheminformatics, St. Petersburg School of Physics, Mathematics and Computer Science, HSE University, 194100 St. Peterburg, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaState Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaDepartment of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, RussiaAlthough the COVID-19 pandemic caused by SARS-CoV-2 viruses is officially over, the search for new effective agents with activity against a wide range of coronaviruses is still an important task for medical chemists and virologists. We synthesized a series of thiazolo-thiophenes based on (+)- and (−)-usnic acid and studied their ability to inhibit the main protease of SARS-CoV-2. Substances containing unsubstituted thiophene groups or methyl- or bromo-substituted thiophene moieties showed moderate activity. Derivatives containing nitro substituents in the thiophene heterocycle—just as pure (+)- and (−)-usnic acids—showed no anti-3CL<sup>pro</sup> activity. Kinetic parameters of the most active compound, <b>(+)-3e</b>, were investigated, and molecular modeling of the possible interaction of the new thiazolo-thiophenes with the active site of the main protease was carried out. We evaluated the binding energies of the ligand and protein in a ligand–protein complex. Active compound <b>(+)-3e</b> was found to bind with minimum free energy; the binding of inactive compound <b>(+)-3g</b> is characterized by higher values of minimum free energy; the positioning of pure (+)-usnic acid proved to be unstable and is accompanied by the formation of intermolecular contacts with many amino acids of the catalytic binding site. Thus, the molecular dynamics results were consistent with the experimental data. In an in vitro antiviral assay against six strains (Wuhan, Delta, and four Omicron sublineages) of SARS-CoV-2, <b>(+)-3e</b> demonstrated pronounced antiviral activity against all the strains.https://www.mdpi.com/1999-4915/16/2/215usnic acidSARS-CoV-2main protease3CL<sup>pro</sup>molecular modeling |
| spellingShingle | Olga I. Yarovaya Aleksandr S. Filimonov Dmitriy S. Baev Sophia S. Borisevich Anna V. Zaykovskaya Varvara Yu. Chirkova Mariya K. Marenina Yulia V. Meshkova Svetlana V. Belenkaya Dmitriy N. Shcherbakov Maxim A. Gureev Olga A. Luzina Oleg V. Pyankov Nariman F. Salakhutdinov Mikhail V. Khvostov The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses Viruses usnic acid SARS-CoV-2 main protease 3CL<sup>pro</sup> molecular modeling |
| title | The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses |
| title_full | The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses |
| title_fullStr | The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses |
| title_full_unstemmed | The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses |
| title_short | The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses |
| title_sort | potential of usnic acid based thiazolo thiophenes as inhibitors of the main protease of sars cov 2 viruses |
| topic | usnic acid SARS-CoV-2 main protease 3CL<sup>pro</sup> molecular modeling |
| url | https://www.mdpi.com/1999-4915/16/2/215 |
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