The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses

The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses Full article

Journal

Viruses
ISSN: 1999-4915

Output data

Year: 2024, Volume: 16, Number: 2, Pages: 215 Pages count : 1 DOI: 10.3390/v16020215

Tags

usnic acid; SARS-CoV-2; main protease; 3CLpro; molecular modeling

Authors

Yarovaya Olga I. ¹ , Filimonov Aleksandr S. ¹ , Baev Dmitriy S. ^1,2 , Borisevich Sophia S. ^2,3 , Zaykovskaya Anna V. ⁴ , Chirkova Varvara Yu. ⁵ , Marenina Mariya K. ¹ , Meshkova Yulia V. ¹ , Belenkaya Svetlana V. ^1,4 , Shcherbakov Dmitriy N. ^1,4,5 , Gureev Maxim A. ⁶ , Luzina Olga A. ¹ , Pyankov Oleg V. ⁴ , Salakhutdinov Nariman F. ¹ , Khvostov Mikhail V. ¹

Affiliations

1	Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia
2	Synchrotron Radiation Facility SKIF, G.K. Boreskov Institute of Catalysis SB RAS, 630559 Koltsovo, Russia
3	Laboratory of Chemical Physics, Ufa Institute of Chemistry, Ufa Federal Research Centre, 450078 Ufa, Russia
4	State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia
5	Institute of Biology and Biotechnology, Altay State University, 656049 Barnaul, Russia
6	Laboratory of Bio- and Cheminformatics, St. Petersburg School of Physics, Mathematics and Computer Science, HSE University, 194100 St. Peterburg, Russia

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-3CLpro activity. Kinetic parameters of the most active compound, (+)-3e, 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 (+)-3e was found to bind with minimum free energy; the binding of inactive compound (+)-3g 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, (+)-3e demonstrated pronounced antiviral activity against all the strains.

Yarovaya O.I. , Filimonov A.S. , Baev D.S. , Borisevich S.S. , Zaykovskaya A.V. , Chirkova V.Y. , Marenina M.K. , Meshkova Y.V. , Belenkaya S.V. , Shcherbakov D.N. , Gureev M.A. , Luzina O.A. , Pyankov O.V. , Salakhutdinov N.F. , Khvostov M.V.
The Potential of Usnic-Acid-Based Thiazolo-Thiophenes as Inhibitors of the Main Protease of SARS-CoV-2 Viruses
Viruses. 2024. V.16. N2. P.215. DOI: 10.3390/v16020215 WOS Scopus OpenAlex

Submitted:	Nov 27, 2023
Accepted:	Jan 25, 2024
Published online:	Jan 31, 2024

Web of science:	WOS:001175196200001
Scopus:	2-s2.0-85185858400
OpenAlex:	W4391403673

DB	Citing
OpenAlex	1
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