110755-51-6Relevant articles and documents
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,Leit?o, Andrei,Lameira, Jer?nimo,Montanari, Carlos A.
, p. 1666 - 1677 (2020)
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.
L -amino acid amides via dynamic kinetic resolution
Tessaro, Davide,Cerioli, Lorenzo,Servi, Stefano,Viani, Fiorenza,D'Arrigo, Paola
, p. 2333 - 2338 (2011/10/19)
Racemic natural and non-natural N-Boc-amino acid thioesters undergo enzyme-catalyzed ammoniolysis and aminolysis with concomitant base-catalyzed racemization of the non-transformed D-enantiomer with the formation of the corresponding L-amides in good yields and excellent enantiomeric purity all above 98% ee. This is the first example of a dynamic kinetic resolution of amino acid derivatives with amides formation. Copyright
Identification of a novel class of succinyl-nitrile-based Cathepsin S inhibitors
Bekkali, Younes,Thomson, David S.,Betageri, Raj,Emmanuel, Michel J.,Hao, Ming-Hong,Hickey, Eugene,Liu, Weimin,Patel, Usha,Ward, Yancey D.,Young, Erick R.R.,Nelson, Richard,Kukulka, Alison,Brown, Maryanne L.,Crane, Kathy,White, Della,Freeman, Dorothy M.,Labadia, Mark E.,Wildeson, Jessi,Spero, Denice M.
, p. 2465 - 2469 (2008/03/11)
The synthesis and in vitro activities of a series of succinyl-nitrile-based inhibitors of Cathepsin S are described. Several members of this class show nanomolar inhibition of the target enzyme as well as cellular potency. The inhibitors displaying the greatest potency contain N-alkyl substituted piperidine and pyrrolidine rings spiro-fused to the α-carbon of the P1 residue.
