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Relative binding energies predict crystallographic binding modes of ethionamide booster lead compounds.

Tatum, N.J. and Duarte, F. and Kamerlin, S.L.C. and Pohl, E. (2019) 'Relative binding energies predict crystallographic binding modes of ethionamide booster lead compounds.', Journal of physical chemistry letters., 10 (9). pp. 2244-2249.

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.

Item Type:Article
Full text:Publisher-imposed embargo
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Full text:(VoR) Version of Record
Available under License - Creative Commons Attribution.
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(2225Kb)
Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1021/acs.jpclett.9b00741
Publisher statement: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.
Date accepted:09 April 2019
Date deposited:10 April 2019
Date of first online publication:09 April 2019
Date first made open access:No date available

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