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Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds

[Image: see text] Transcriptional repressor EthR from Mycobacterium tuberculosis is a valuable target for antibiotic booster drugs. We previously reported a virtual screening campaign to identify EthR inhibitors for development. Two ligand binding orientations were often proposed, though only the to...

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Autores principales: Tatum, Natalie J., Duarte, Fernanda, Kamerlin, Shina C. L., Pohl, Ehmke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503467/
https://www.ncbi.nlm.nih.gov/pubmed/30965004
http://dx.doi.org/10.1021/acs.jpclett.9b00741
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author Tatum, Natalie J.
Duarte, Fernanda
Kamerlin, Shina C. L.
Pohl, Ehmke
author_facet Tatum, Natalie J.
Duarte, Fernanda
Kamerlin, Shina C. L.
Pohl, Ehmke
author_sort Tatum, Natalie J.
collection PubMed
description [Image: see text] Transcriptional repressor EthR from Mycobacterium tuberculosis is a valuable target for antibiotic booster drugs. We previously reported a virtual screening campaign to identify EthR inhibitors for development. Two ligand binding orientations were often proposed, though only the top scoring pose was utilized for filtering of the large data set. We obtained biophysically validated hits, some of which yielded complex crystal structures. In some cases, the crystallized binding mode and top scoring mode agree, while for others an alternate ligand binding orientation was found. In this contribution, we combine rigid docking, molecular dynamics simulations, and the linear interaction energy method to calculate binding free energies and derive relative binding energies for a number of EthR inhibitors in both modes. This strategy allowed us to correctly predict the most favorable orientation. Therefore, this widely applicable approach will be suitable to triage multiple binding modes within EthR and other potential drug targets with similar characteristics.
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spelling pubmed-65034672019-05-08 Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds Tatum, Natalie J. Duarte, Fernanda Kamerlin, Shina C. L. Pohl, Ehmke J Phys Chem Lett [Image: see text] Transcriptional repressor EthR from Mycobacterium tuberculosis is a valuable target for antibiotic booster drugs. We previously reported a virtual screening campaign to identify EthR inhibitors for development. Two ligand binding orientations were often proposed, though only the top scoring pose was utilized for filtering of the large data set. We obtained biophysically validated hits, some of which yielded complex crystal structures. In some cases, the crystallized binding mode and top scoring mode agree, while for others an alternate ligand binding orientation was found. In this contribution, we combine rigid docking, molecular dynamics simulations, and the linear interaction energy method to calculate binding free energies and derive relative binding energies for a number of EthR inhibitors in both modes. This strategy allowed us to correctly predict the most favorable orientation. Therefore, this widely applicable approach will be suitable to triage multiple binding modes within EthR and other potential drug targets with similar characteristics. American Chemical Society 2019-04-09 2019-05-02 /pmc/articles/PMC6503467/ /pubmed/30965004 http://dx.doi.org/10.1021/acs.jpclett.9b00741 Text en Copyright © 2019 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle Tatum, Natalie J.
Duarte, Fernanda
Kamerlin, Shina C. L.
Pohl, Ehmke
Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds
title Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds
title_full Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds
title_fullStr Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds
title_full_unstemmed Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds
title_short Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds
title_sort relative binding energies predict crystallographic binding modes of ethionamide booster lead compounds
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503467/
https://www.ncbi.nlm.nih.gov/pubmed/30965004
http://dx.doi.org/10.1021/acs.jpclett.9b00741
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