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Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques
In this study, we investigate the atomistic details of Keap1-Nrf2 inhibitors by in-depth modeling techniques, including molecular dynamics (MD) simulations, and the path-based free energy method of umbrella sampling (US). The protein–protein interaction (PPI) of Keap1-Nrf2 is implicated in several n...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891428/ https://www.ncbi.nlm.nih.gov/pubmed/31726716 http://dx.doi.org/10.3390/molecules24224085 |
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author | Londhe, Ashwini Machhindra Gadhe, Changdev Gorakshnath Lim, Sang Min Pae, Ae Nim |
author_facet | Londhe, Ashwini Machhindra Gadhe, Changdev Gorakshnath Lim, Sang Min Pae, Ae Nim |
author_sort | Londhe, Ashwini Machhindra |
collection | PubMed |
description | In this study, we investigate the atomistic details of Keap1-Nrf2 inhibitors by in-depth modeling techniques, including molecular dynamics (MD) simulations, and the path-based free energy method of umbrella sampling (US). The protein–protein interaction (PPI) of Keap1-Nrf2 is implicated in several neurodegenerative diseases like cancer, diabetes, and cardiomyopathy. A better understanding of the five sub-pocket binding sites for Nrf2 (ETGE and DLG motifs) inside the Kelch domain would expedite the inhibitor design process. We selected four protein–ligand complexes with distinct co-crystal ligands and binding occupancies inside the Nrf2 binding site. We performed 100 ns of MD simulation for each complex and analyzed the trajectories. From the results, it is evident that one ligand (1VV) has flipped inside the binding pocket, whereas the remaining three were stable. We found that Coulombic (Arg483, Arg415, Ser363, Ser508, and Ser602) and Lennard–Jones (Tyr525, Tyr334, and Tyr572) interactions played a significant role in complex stability. The obtained binding free energy values from US simulations were consistent with the potencies of simulated ligands. US simulation highlight the importance of basic and aromatic residues in the binding pocket. A detailed description of the dissociation process brings valuable insight into the interaction of the four selected protein–ligand complexes, which could help in the future to design more potent PPI inhibitors. |
format | Online Article Text |
id | pubmed-6891428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68914282019-12-18 Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques Londhe, Ashwini Machhindra Gadhe, Changdev Gorakshnath Lim, Sang Min Pae, Ae Nim Molecules Article In this study, we investigate the atomistic details of Keap1-Nrf2 inhibitors by in-depth modeling techniques, including molecular dynamics (MD) simulations, and the path-based free energy method of umbrella sampling (US). The protein–protein interaction (PPI) of Keap1-Nrf2 is implicated in several neurodegenerative diseases like cancer, diabetes, and cardiomyopathy. A better understanding of the five sub-pocket binding sites for Nrf2 (ETGE and DLG motifs) inside the Kelch domain would expedite the inhibitor design process. We selected four protein–ligand complexes with distinct co-crystal ligands and binding occupancies inside the Nrf2 binding site. We performed 100 ns of MD simulation for each complex and analyzed the trajectories. From the results, it is evident that one ligand (1VV) has flipped inside the binding pocket, whereas the remaining three were stable. We found that Coulombic (Arg483, Arg415, Ser363, Ser508, and Ser602) and Lennard–Jones (Tyr525, Tyr334, and Tyr572) interactions played a significant role in complex stability. The obtained binding free energy values from US simulations were consistent with the potencies of simulated ligands. US simulation highlight the importance of basic and aromatic residues in the binding pocket. A detailed description of the dissociation process brings valuable insight into the interaction of the four selected protein–ligand complexes, which could help in the future to design more potent PPI inhibitors. MDPI 2019-11-12 /pmc/articles/PMC6891428/ /pubmed/31726716 http://dx.doi.org/10.3390/molecules24224085 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Londhe, Ashwini Machhindra Gadhe, Changdev Gorakshnath Lim, Sang Min Pae, Ae Nim Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques |
title | Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques |
title_full | Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques |
title_fullStr | Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques |
title_full_unstemmed | Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques |
title_short | Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques |
title_sort | investigation of molecular details of keap1-nrf2 inhibitors using molecular dynamics and umbrella sampling techniques |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891428/ https://www.ncbi.nlm.nih.gov/pubmed/31726716 http://dx.doi.org/10.3390/molecules24224085 |
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