First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones
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Otros documentos de la autoría: Arafet Cruz, Kemel; Ferrer Castillo, Silvia; Moliner, Vicent
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Título
First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl KetonesFecha de publicación
2015-05-12Editor
ACS PublicationsISSN
0006-2960Cita bibliográfica
ARAFET, Kemel; FERRER, Silvia; MOLINER, Vicent. First Quantum Mechanics/Molecular Mechanics Studies of the Inhibition Mechanism of Cruzain by Peptidyl Halomethyl Ketones. Biochemistry, 2015, vol. 54, no 21, p. 3381-3391.Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
http://pubs.acs.org/doi/abs/10.1021/bi501551gVersión
info:eu-repo/semantics/acceptedVersionPalabras clave / Materias
Resumen
Cruzain is a primary cysteine protease expressed by the protozoan
parasite Trypanosoma cruzi during Chagas disease infection, and thus, the development
of inhibitors of this protein is a promising target for designing ... [+]
Cruzain is a primary cysteine protease expressed by the protozoan
parasite Trypanosoma cruzi during Chagas disease infection, and thus, the development
of inhibitors of this protein is a promising target for designing an effective therapy
against the disease. In this paper, the mechanism of inhibition of cruzain by two
different irreversible peptidyl halomethyl ketones (PHK) inhibitors has been studied by
means of hybrid quantum mechanics/molecular mechanics−molecular dynamics (MD)
simulations to obtain a complete representation of the possible free energy reaction
paths. These have been traced on free energy surfaces in terms of the potential of mean
force computed at AM1d/MM and DFT/MM levels of theory. An analysis of the
possible reaction mechanisms of the inhibition process has been performed showing
that the nucleophilic attack of an active site cysteine, Cys25, on a carbon atom of the
inhibitor and the cleavage of the halogen−carbon bond take place in a single step. PClK
appears to be much more favorable than PFK from a kinetic point of view. This result
would be in agreement with experimental studies in other papain-like enzymes. A deeper analysis of the results suggests that the
origin of the differences between PClK and PFK can be the different stabilizing interactions established between the inhibitors
and the residues of the active site of the protein. Any attempt to explore the viability of the inhibition process through a stepwise
mechanism involving the formation of a thiohemiketal intermediate and a three-membered sulfonium intermediate has been
unsuccessful. Nevertheless, a mechanism through a protonated thiohemiketal, with participation of His159 as a proton donor,
appears to be feasible despite showing higher free energy barriers. Our results suggest that PClK can be used as a starting point to
develop a proper inhibitor of cruzain. [-]
Publicado en
Biochemistry, 2015, vol. 54, no 21Derechos de acceso
Copyright © 2015 American Chemical Society
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