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

Autor:	Yarovaya OI; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia., Filimonov AS; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia., Baev DS; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia.; Synchrotron Radiation Facility SKIF, G.K. Boreskov Institute of Catalysis SB RAS, 630559 Koltsovo, Russia., Borisevich SS; Synchrotron Radiation Facility SKIF, G.K. Boreskov Institute of Catalysis SB RAS, 630559 Koltsovo, Russia.; Laboratory of Chemical Physics, Ufa Institute of Chemistry, Ufa Federal Research Centre, 450078 Ufa, Russia., Zaykovskaya AV; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia., Chirkova VY; Institute of Biology and Biotechnology, Altay State University, 656049 Barnaul, Russia., Marenina MK; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia., Meshkova YV; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia., Belenkaya SV; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia.; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia., Shcherbakov DN; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia.; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia.; Institute of Biology and Biotechnology, Altay State University, 656049 Barnaul, Russia., Gureev MA; Laboratory of Bio- and Cheminformatics, St. Petersburg School of Physics, Mathematics and Computer Science, HSE University, 194100 St. Peterburg, Russia., Luzina OA; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia., Pyankov OV; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia., Salakhutdinov NF; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia., Khvostov MV; Department of Medicinal Chemistry, N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090 Novosibirsk, Russia.
Jazyk:	angličtina
Zdroj:	Viruses [Viruses] 2024 Jan 31; Vol. 16 (2). Date of Electronic Publication: 2024 Jan 31.
DOI:	10.3390/v16020215
Abstrakt:	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 pro 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.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.