Covalent Inhibition of the Human 20S Proteasome with Homobelactosin C Inquired by QM/MM Studies
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Altres documents de l'autoria: Serrano Aparicio, Natalia; Ferrer, Silvia; Świderek, Katarzyna
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INVESTIGACIONMetadades
Títol
Covalent Inhibition of the Human 20S Proteasome with Homobelactosin C Inquired by QM/MM StudiesData de publicació
2022Editor
MDPIISSN
1424-8247Cita bibliogràfica
Serrano-Aparicio, N.; Ferrer, S.; Swiderek, K. Covalent Inhibition ´ of the Human 20S Proteasome with Homobelactosin C Inquired by QM/MM Studies. Pharmaceuticals 2022, 15, 531. https://doi.org/ 10.3390/ph15050531Tipus de document
info:eu-repo/semantics/articleVersió
info:eu-repo/semantics/publishedVersionParaules clau / Matèries
Resum
20S proteasome is a main player in the protein degradation pathway in the cytosol, thus
intervening in multiple pivotal cellular processes. Over the years the proteasome has emerged as a
crucial target for the ... [+]
20S proteasome is a main player in the protein degradation pathway in the cytosol, thus
intervening in multiple pivotal cellular processes. Over the years the proteasome has emerged as a
crucial target for the treatment of many diseases such as neurodegenerative diseases, cancer, autoimmune diseases, developmental disorders, cystic fibrosis, diabetes, cardiac diseases, atherosclerosis,
and aging. In this work, the mechanism of proteasome covalent inhibition with bisbenzyl-protected
homobelactosin C (hBelC) was explored using quantum mechanics/molecular mechanics (QM/MM)
methods. Molecular dynamic simulations were used to describe key interactions established between
the hBelC and its unique binding mode in the primed site of the β5 subunit. The free energy surfaces
were computed to characterize the kinetics and thermodynamics of the inhibition process. This study
revealed that although the final inhibition product for hBelC is formed according to the same molecular mechanism as one described for hSalA, the free energy profile of the reaction pathway differs
significantly from the one previously reported for γ-lactam-β-lactone containing inhibitors in terms
of the height of the activation barrier as well as the stabilization of the final product. Moreover, it was
proved that high stabilization of the covalent adduct formed between β5-subunit and hBelC, together
with the presence of aminocarbonyl side chain in the structure of the inhibitor which prevents the
hydrolysis of the ester bond from taking place, determines its irreversible character. [-]
Publicat a
Pharmaceuticals 2022, 15, 531Entitat finançadora
Ministerio de Ciencia, Innovación y Universidades | Generalitat Valenciana | Universitat Jaume I
Codi del projecte o subvenció
PID2019-107098RJ-I00 | SEJI/2020/007 | UJI-A2019-04 | RYC2020-030596-I
Drets d'accés
info:eu-repo/semantics/openAccess
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