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Cysteine protease inhibition by nitrile-based inhibitors: a computational study
Cysteine protease enzymes are important for human physiology and catalyze key protein degradation pathways. These enzymes react via a nucleophilic reaction mechanism that involves a cysteine residue and the proton of a proximal histidine. Particularly efficient inhibitors of these enzymes are nitril...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982517/ https://www.ncbi.nlm.nih.gov/pubmed/24790966 http://dx.doi.org/10.3389/fchem.2013.00039 |
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author | Quesne, Matthew G. Ward, Richard A. de Visser, Sam P. |
author_facet | Quesne, Matthew G. Ward, Richard A. de Visser, Sam P. |
author_sort | Quesne, Matthew G. |
collection | PubMed |
description | Cysteine protease enzymes are important for human physiology and catalyze key protein degradation pathways. These enzymes react via a nucleophilic reaction mechanism that involves a cysteine residue and the proton of a proximal histidine. Particularly efficient inhibitors of these enzymes are nitrile-based, however, the details of the catalytic reaction mechanism currently are poorly understood. To gain further insight into the inhibition of these molecules, we have performed a combined density functional theory and quantum mechanics/molecular mechanics study on the reaction of a nitrile-based inhibitor with the enzyme active site amino acids. We show here that small perturbations to the inhibitor structure can have dramatic effects on the catalysis and inhibition processes. Thus, we investigated a range of inhibitor templates and show that specific structural changes reduce the inhibitory efficiency by several orders of magnitude. Moreover, as the reaction takes place on a polar surface, we find strong differences between the DFT and QM/MM calculated energetics. In particular, the DFT model led to dramatic distortions from the starting structure and the convergence to a structure that would not fit the enzyme active site. In the subsequent QM/MM study we investigated the use of mechanical vs. electronic embedding on the kinetics, thermodynamics and geometries along the reaction mechanism. We find minor effects on the kinetics of the reaction but large geometric and thermodynamics differences as a result of inclusion of electronic embedding corrections. The work here highlights the importance of model choice in the investigation of this biochemical reaction mechanism. |
format | Online Article Text |
id | pubmed-3982517 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-39825172014-04-30 Cysteine protease inhibition by nitrile-based inhibitors: a computational study Quesne, Matthew G. Ward, Richard A. de Visser, Sam P. Front Chem Chemistry Cysteine protease enzymes are important for human physiology and catalyze key protein degradation pathways. These enzymes react via a nucleophilic reaction mechanism that involves a cysteine residue and the proton of a proximal histidine. Particularly efficient inhibitors of these enzymes are nitrile-based, however, the details of the catalytic reaction mechanism currently are poorly understood. To gain further insight into the inhibition of these molecules, we have performed a combined density functional theory and quantum mechanics/molecular mechanics study on the reaction of a nitrile-based inhibitor with the enzyme active site amino acids. We show here that small perturbations to the inhibitor structure can have dramatic effects on the catalysis and inhibition processes. Thus, we investigated a range of inhibitor templates and show that specific structural changes reduce the inhibitory efficiency by several orders of magnitude. Moreover, as the reaction takes place on a polar surface, we find strong differences between the DFT and QM/MM calculated energetics. In particular, the DFT model led to dramatic distortions from the starting structure and the convergence to a structure that would not fit the enzyme active site. In the subsequent QM/MM study we investigated the use of mechanical vs. electronic embedding on the kinetics, thermodynamics and geometries along the reaction mechanism. We find minor effects on the kinetics of the reaction but large geometric and thermodynamics differences as a result of inclusion of electronic embedding corrections. The work here highlights the importance of model choice in the investigation of this biochemical reaction mechanism. Frontiers Media S.A. 2013-12-27 /pmc/articles/PMC3982517/ /pubmed/24790966 http://dx.doi.org/10.3389/fchem.2013.00039 Text en Copyright © 2013 Quesne, Ward and de Visser. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Chemistry Quesne, Matthew G. Ward, Richard A. de Visser, Sam P. Cysteine protease inhibition by nitrile-based inhibitors: a computational study |
title | Cysteine protease inhibition by nitrile-based inhibitors: a computational study |
title_full | Cysteine protease inhibition by nitrile-based inhibitors: a computational study |
title_fullStr | Cysteine protease inhibition by nitrile-based inhibitors: a computational study |
title_full_unstemmed | Cysteine protease inhibition by nitrile-based inhibitors: a computational study |
title_short | Cysteine protease inhibition by nitrile-based inhibitors: a computational study |
title_sort | cysteine protease inhibition by nitrile-based inhibitors: a computational study |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982517/ https://www.ncbi.nlm.nih.gov/pubmed/24790966 http://dx.doi.org/10.3389/fchem.2013.00039 |
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