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Durham University

Department of Biosciences


Publication details for Prof. Ehmke Pohl

Tatum, NJ, Duarte, F, Kamerlin, SLC & Pohl, E (2019). Relative Binding Energies Predict Crystallographic Binding Modes of Ethionamide Booster Lead Compounds. The Journal of Physical Chemistry Letters 10(9): 2244–2249.

Author(s) from Durham


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.