Inhibition studies on the human 20s proteasome: molecular insights from a computational approach

• Autores: Natalia Serrano Aparicio
• Directores de la Tesis: Katarzyna Świderek (dir. tes.), Vicente Moliner Ibáñez (dir. tes.)
• Lectura: En la Universitat Jaume I ( España ) en 2022
• Idioma: español
• Tribunal Calificador de la Tesis: José Javier Ruiz Pernía (presid.), Raquel Castillo Solsona (secret.), Tiziana Marino (voc.)
• Programa de doctorado: Programa de Doctorado en Química Teórica y Modelización Computacional/Theoretical Chemistry and Computational Modelling por la Universidad Autónoma de Madrid; la Universidad Complutense de Madrid; la Universidad de Barcelona; la Universidad de Cantabria; la Universidad de Extremadura; la Universidad de las Illes Balears; la Universidad de Murcia; la Universidad de Oviedo; la Universidad de Sevilla; la Universidad de Vigo; la Universidad del País Vasco/Euskal Herriko Unibertsitatea; la Universidad Jaume I de Castellón y la Universitat de València (Estudi General)
• Materias:
  • Física
    • Química física
      • Catálisis
    • Física del estado sólido
  • Química
    • Bioquímica
      • Biología molecular
• Enlaces
  • Tesis en acceso abierto en: TDX
• Resumen

  • The human 20S proteasome activity and malfunction has been related to numerous diseases and validated as a protein target for inhibition in the treatment of cancer, with three proteasome inhibitors approved as a drug. But these compounds could be improved, since usually the molecular mechanism of action is unknown. Thus, computational studies can clarify the mode of action of proteasome inhibitors, helping to understand the system and improve the inhibition process The present thesis is devoted to understand the mode of action of two classes of covalent inhibitors of the 20S proteasome, α,β-epoxyketones and γ-lactam-β-lactones. Molecular dynamics simulations with hybrid QM/MM potentials have been used to characterize the free energy landscape for the inhibition mechanism of these compounds and to provide the structures necessary to analyze and understand the inhibition process in the β5 active site of the proteasome, providing valuable knowledge to optimize the compounds into more efficient inhibitors.