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

Tatum, NJ; Duarte, F; Kamerlin, SLC; Pohl, E

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


Authors

NJ Tatum

F Duarte

SLC Kamerlin



Abstract

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 utilised for filtering of the large dataset. We obtained biophysically validated hits, some which yielded complex crystal structures. In some cases, the crystallised binding mode and top scoring mode agree, while for others the alternate ligand binding orientation was found. In this contribution we combine rigid docking, MD simulations and the LIE method to calculate free energies of binding and derive relative binding energies for a number of EthR inhibitors in both modes. This strategy allowed us to correctly predict the most favourable orientation. Therefore, this widely applicable approach will be suitable to triage multiple binding modes within EthR and other potential drug targets with similar characteristics.

Citation

Tatum, N., Duarte, F., Kamerlin, S., & Pohl, E. (2019). Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds. Journal of Physical Chemistry Letters, 10(9), 2244-2249. https://doi.org/10.1021/acs.jpclett.9b00741

Journal Article Type Article
Acceptance Date Apr 9, 2019
Online Publication Date Apr 9, 2019
Publication Date May 2, 2019
Deposit Date Apr 10, 2019
Publicly Available Date Mar 29, 2024
Journal Journal of Physical Chemistry Letters
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 10
Issue 9
Pages 2244-2249
DOI https://doi.org/10.1021/acs.jpclett.9b00741

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Advance online version This is an open access article published under a Creative Commons Attribution (CC-BY)
License, which permits unrestricted use, distribution and reproduction in any medium,
provided the author and source are cited.






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