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

Tatum, Natalie J ; Duarte, Fernanda ; Kamerlin, Shina C L LU orcid and Pohl, Ehmke (2019) In The Journal of Physical Chemistry Letters 10(9). p.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 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... (More)

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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author
; ; and
publishing date
type
Contribution to journal
publication status
published
in
The Journal of Physical Chemistry Letters
volume
10
issue
9
pages
6 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:30965004
  • scopus:85065210507
ISSN
1948-7185
DOI
10.1021/acs.jpclett.9b00741
language
English
LU publication?
no
id
42bd164a-6773-4481-847e-1a44f8492606
date added to LUP
2025-01-11 20:28:06
date last changed
2025-04-06 11:17:38
@article{42bd164a-6773-4481-847e-1a44f8492606,
  abstract     = {{<p>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.</p>}},
  author       = {{Tatum, Natalie J and Duarte, Fernanda and Kamerlin, Shina C L and Pohl, Ehmke}},
  issn         = {{1948-7185}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{9}},
  pages        = {{2244--2249}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{The Journal of Physical Chemistry Letters}},
  title        = {{Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds}},
  url          = {{http://dx.doi.org/10.1021/acs.jpclett.9b00741}},
  doi          = {{10.1021/acs.jpclett.9b00741}},
  volume       = {{10}},
  year         = {{2019}},
}