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Experimental study and computational modelling of cruzain cysteine protease inhibition by dipeptidyl nitriles


Alberto Monteiro Dos Santos

Lorenzo Cianni

Daniela De Vita

Fabiana Rosini


Professor of Computational Pharmaceutical Science


Carlos A. Montanari


Chagas disease affects millions of people in Latin America. This disease is caused by the protozoan parasite Trypanossoma cruzi. The cysteine protease cruzain is a key enzyme for the survival and propagation of this parasite lifecycle. Nitrile-based inhibitors are efficient inhibitors of cruzain that bind by forming a covalent bond with this enzyme. Here, three nitrile-based inhibitors dubbed Neq0409, Neq0410 and Neq0570 were synthesized, and the thermodynamic profile of the bimolecular interaction with cruzain was determined using isothermal titration calorimetry (ITC). The result suggests the inhibition process is enthalpy driven, with a detrimental contribution of entropy. In addition, we have used hybrid Quantum Mechanical/Molecular Mechanical (QM/MM) and Molecular Dynamics (MD) simulations to investigate the reaction mechanism of reversible covalent modification of cruzain by Neq0409, Neq0410 and Neq0570. The computed free energy profile shows that the nucleophilic attack of Cys25 on the carbon C1 of inhibitiors and the proton transfer from His162 to N1 of the dipeptidyl nitrile inhibitor take place in a single step. The calculated free energy of the inhibiton reaction is in agreement with covalent experimental binding. Altogether, the results reported here suggests that nitrile-based inhibitors are good candidates for the development of reversible covalent inhibitors of cruzain and other cysteine proteases.


Dos Santos, A. M., Cianni, L., De Vita, D., Rosini, F., Leitão, A., Laughton, C. A., …Montanari, C. A. (2018). Experimental study and computational modelling of cruzain cysteine protease inhibition by dipeptidyl nitriles. Physical Chemistry Chemical Physics, 20(37), 24317-24328.

Journal Article Type Article
Acceptance Date Sep 6, 2018
Online Publication Date Sep 6, 2018
Publication Date Oct 7, 2018
Deposit Date Nov 27, 2018
Publicly Available Date Sep 7, 2019
Journal Physical Chemistry Chemical Physics
Print ISSN 1463-9076
Electronic ISSN 1463-9084
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 20
Issue 37
Pages 24317-24328
Keywords Physical and theoretical chemistry; General physics and astronomy
Public URL
Publisher URL!divAbstract


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