Quantum mechanics/molecular mechanics studies of the mechanism of cysteine protease inhibition by peptidyl-2,3-epoxyketones
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Other documents of the author: Arafet Cruz, Kemel; Ferrer Castillo, Silvia; González, Florenci; Moliner, Vicent
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comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
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Title
Quantum mechanics/molecular mechanics studies of the mechanism of cysteine protease inhibition by peptidyl-2,3-epoxyketonesDate
2017Publisher
Royal Society of ChemistryISSN
1463-9076; 1463-9084Type
info:eu-repo/semantics/articleVersion
info:eu-repo/semantics/publishedVersionAbstract
Cysteine proteases are the most abundant proteases in parasitic protozoa and they are essential
enzymes to the life cycle of several of them, thus becoming attractive therapeutic targets for the
development of new ... [+]
Cysteine proteases are the most abundant proteases in parasitic protozoa and they are essential
enzymes to the life cycle of several of them, thus becoming attractive therapeutic targets for the
development of new inhibitors. In this paper, a computational study of the inhibition mechanism of
cysteine protease by dipeptidyl-2,3-epoxyketone Cbz-Phe-Hph-(S), a recently proposed inhibitor, has
been carried out by means of molecular dynamics (MD) simulations with hybrid QM/MM potentials. The
computed free energy surfaces of the inhibition mechanism of cysteine proteases by peptidyl
epoxyketones showing how the activation of the epoxide ring and the attack of Cys25 on either C2 or
C3 atoms take place in a concerted manner. According to our results, the acid species responsible for
the protonation of the oxygen atom of the ring would be able to conserve His159, in contrast to
previous studies that proposed a water molecule as the activating species. The low activation free
energies for the reaction where Cys25 attacks the C2 atom of the epoxide ring (12.1 kcal mol1
) or to
the C3 atom (15.4 kcal mol1
), together with the high negative reaction energies suggest that the
derivatives of peptidyl-2,3-epoxyketones can be used to develop new potent inhibitors for the treatment
of Chagas disease. [-]
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Phys. Chem. Chem. Phys., 2017, 19, 12740Rights
This journal is © the Owner Societies 2017. Phys. Chem. Chem.
Phys., 2017,19, 12740-12748 DOI: 10.1039/c7cp01726j - Reproduced by permission of The Royal Society of Chemistry.
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