Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes
comunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/7013
comunitat-uji-handle3:10234/8638
comunitat-uji-handle4:
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https://doi.org/10.1002/chem.201904513 |
Metadata
Title
Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl NitroalkenesDate
2020-02-11Publisher
WileyISSN
0947-6539; 1521-3765Type
info:eu-repo/semantics/articleVersion
info:eu-repo/semantics/publishedVersionSubject
Abstract
In this work a computational study of the mechanism of inhibition of cruzain, rhodesain, and cathepsin L cysteine proteases by the dipeptidyl nitroalkene Cbz‐Phe‐Ala‐CH=CH‐NO2 has been carried out by means of molecular ... [+]
In this work a computational study of the mechanism of inhibition of cruzain, rhodesain, and cathepsin L cysteine proteases by the dipeptidyl nitroalkene Cbz‐Phe‐Ala‐CH=CH‐NO2 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The free‐energy surfaces confirmed that the inhibition takes place by the formation of a covalent bond between the protein and the β‐carbon atom of the inhibitor. According to the results, the tested inhibitor should be a much more efficient inhibitor of cruzain than of rhodesain, and little activity would be expected against cathepsin L, in total correspondence with the available experimental data. The origin of these differences may lie in the different stabilizing electrostatic interactions established between the inhibitor and the residues of the active site and S2 pocket of these enzymes. These results may be useful for the rational design of new dipeptidyl nitroalkenes with higher and more selective inhibitory activity against cysteine proteases. [-]
Is part of
Chemistry–A European Journal, 2020, vol. 26, no 9Investigation project
Ministerio de Ciencia, Innovación y Universidades. Grant Number: PGC2018-094852-B-C21; Universitat Jaume I. Grant Numbers: UJI·B2017-31, UJI·B2018-41, POSDOC-A/2018/30; Generalitat Valenciana. Grant Number: AICO/2019/195Rights
Copyright © John Wiley & Sons, Inc.
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http://rightsstatements.org/vocab/InC/1.0/
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This item appears in the folowing collection(s)
- QUIO_Articles [694]
- QUIO_Articles [694]
- QFA_Articles [819]
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