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Assessment of the Cruzain Cysteine Protease Reversible and Irreversible Covalent Inhibition Mechanism

Silva, José Rogério A ; Cianni, Lorenzo ; Araujo, Deborah ; Batista, Pedro Henrique Jatai ; de Vita, Daniela ; Rosini, Fabiana ; Leitão, Andrei ; Lameira, Jerônimo ; Montanari, Carlos A

Journal of chemical information and modeling, 2020-03, Vol.60 (3), p.1666-1677 [Periódico revisado por pares]

United States: American Chemical Society

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  • Título:
    Assessment of the Cruzain Cysteine Protease Reversible and Irreversible Covalent Inhibition Mechanism
  • Autor: Silva, José Rogério A ; Cianni, Lorenzo ; Araujo, Deborah ; Batista, Pedro Henrique Jatai ; de Vita, Daniela ; Rosini, Fabiana ; Leitão, Andrei ; Lameira, Jerônimo ; Montanari, Carlos A
  • Assuntos: Computer simulation ; Coordination compounds ; Covalence ; Cysteine ; Free energy ; Ligands ; Mathematical analysis ; Molecular dynamics ; Protease ; Protease inhibitors ; Quantum mechanics ; Titration ; Titration calorimetry
  • É parte de: Journal of chemical information and modeling, 2020-03, Vol.60 (3), p.1666-1677
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: Reversible and irreversible covalent ligands are advanced cysteine protease inhibitors in the drug development pipeline. K777 is an irreversible inhibitor of cruzain, a necessary enzyme for the survival of the Trypanosoma cruzi (T. cruzi) parasite, the causative agent of Chagas disease. Despite their importance, irreversible covalent inhibitors are still often avoided due to the risk of adverse effects. Herein, we replaced the K777 vinyl sulfone group with a nitrile moiety to obtain a reversible covalent inhibitor (Neq0682) of cysteine protease. Then, we used advanced experimental and computational techniques to explore details of the inhibition mechanism of cruzain by reversible and irreversible inhibitors. The isothermal titration calorimetry (ITC) analysis shows that inhibition of cruzain by an irreversible inhibitor is thermodynamically more favorable than by a reversible one. The hybrid Quantum Mechanics/Molecular Mechanics (QM/MM) and Molecular Dynamics (MD) simulations were used to explore the mechanism of the reaction inhibition of cruzain by K777 and Neq0682. The calculated free energy profiles show that the Cys25 nucleophilic attack and His162 proton transfer occur in a single step for a reversible inhibitor and two steps for an irreversible covalent inhibitor. The hybrid QM/MM calculated free energies for the inhibition reaction correspond to −26.7 and −5.9 kcal mol–1 for K777 and Neq0682 at the MP2/MM level, respectively. These results indicate that the ΔG of the reaction is very negative for the process involving K777, consequently, the covalent adduct cannot revert to a noncovalent protein–ligand complex, and its binding tends to be irreversible. Overall, the present study provides insights into a covalent inhibition mechanism of cysteine proteases.
  • Editor: United States: American Chemical Society
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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