Next Article in Journal
Sequential Response of Sage Antioxidant Metabolism to Chilling Treatment
Next Article in Special Issue
Identification of The Fipronil Resistance Associated Mutations in Nilaparvata lugens GABA Receptors by Molecular Modeling
Previous Article in Journal
Speciation Studies of Bifunctional 3-Hydroxy-4-Pyridinone Ligands in the Presence of Zn2+ at Different Ionic Strengths and Temperatures
Previous Article in Special Issue
Pharmacophoric Site Identification and Inhibitor Design for Autotaxin
Open AccessArticle

Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques

1
Convergence Research Center for Diagnosis, Treatment, and Care system of Dementia, Korea Institute of Science and Technology, Seoul 02792, Korea
2
Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Korea
*
Author to whom correspondence should be addressed.
Academic Editor: Sandra Gemma
Molecules 2019, 24(22), 4085; https://doi.org/10.3390/molecules24224085
Received: 7 September 2019 / Revised: 31 October 2019 / Accepted: 9 November 2019 / Published: 12 November 2019
(This article belongs to the Special Issue Structure-Based Design of Biologically Active Compounds)
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. View Full-Text
Keywords: Keap1-NRF2 inhibitors; PPI inhibition; molecular modeling; MD simulations; US simulation; binding free energy Keap1-NRF2 inhibitors; PPI inhibition; molecular modeling; MD simulations; US simulation; binding free energy
Show Figures

Graphical abstract

MDPI and ACS Style

Londhe, A.M.; Gadhe, C.G.; Lim, S.M.; Pae, A.N. Investigation of Molecular Details of Keap1-Nrf2 Inhibitors Using Molecular Dynamics and Umbrella Sampling Techniques. Molecules 2019, 24, 4085.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop