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Molecular mechanism of labelling functional cysteines by heterocyclic thiones [Elektronski vir]Mihalovits, Levente M. ...Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in ... labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines. We chose the main protease of SARS-CoV-2 harboring Cys145 at the active site that is a structurally characterized and clinically validated target of covalent inhibitors. We screened an in-house, cysteine-targeting covalent inhibitor library which resulted in several covalent fragment hits with benzoxazole, benzothiazole and benzimidazole cores. Thione derivatives and Michael acceptors were selected for further investigations with the objective of exploring the mechanism of inhibition of the thiones and using the thoroughly characterized Michael acceptors for benchmarking our studies. Classical and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were carried out that revealed a new mechanism of covalent cysteine labelling by thione derivatives, which was supported by QM and free energy calculations and by a wide range of experimental results. Our study shows that the molecular recognition step plays a crucial role in the overall binding of both sets of molecules.Vir: ChemPhysChem [Elektronski vir]. - ISSN 1439-7641 (Vol. 25, no. 1, art. e202300596, 2024, 11 str.)Vrsta gradiva - e-članek ; neleposlovje za odrasleLeto - 2024Jezik - angleškiCOBISS.SI-ID - 171662083
Avtor
Mihalovits, Levente M. |
Kollár, Levente |
Bajusz, Dávid |
Knez, Damijan, farmacevt |
Bozovičar, Krištof |
Imre, Tímea |
Ferenczy, György G. |
Gobec, Stanislav, 1970- |
Keserü M., György
Teme
SARS-CoV-2 |
3CLpro covalent inhibitors |
QM/MM molecular dynamics |
SARS-CoV-2 |
thermodynamic integration |
umbrella sampling |
3CLpro kovalentni inhibitorji |
QM/MM molekularna dinamika |
termodinamična integracija |
krovno vzorčenje
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Baze podatkov, v katerih je revija indeksirana
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Mihalovits, Levente M. | ![]() |
Kollár, Levente | ![]() |
Bajusz, Dávid | ![]() |
Knez, Damijan, farmacevt | 36438 |
Bozovičar, Krištof | 53738 |
Imre, Tímea | ![]() |
Ferenczy, György G. | ![]() |
Gobec, Stanislav, 1970- | 15284 |
Keserü M., György | ![]() |
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