Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Londhe, Ashwini Machhindra, Gadhe, Changdev Gorakshnath, Lim, Sang Min, Pae, Ae Nim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
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
_version_ 1783475811508027392
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
work_keys_str_mv AT londheashwinimachhindra investigationofmoleculardetailsofkeap1nrf2inhibitorsusingmoleculardynamicsandumbrellasamplingtechniques
AT gadhechangdevgorakshnath investigationofmoleculardetailsofkeap1nrf2inhibitorsusingmoleculardynamicsandumbrellasamplingtechniques
AT limsangmin investigationofmoleculardetailsofkeap1nrf2inhibitorsusingmoleculardynamicsandumbrellasamplingtechniques
AT paeaenim investigationofmoleculardetailsofkeap1nrf2inhibitorsusingmoleculardynamicsandumbrellasamplingtechniques