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

DOI: 10.1021/acs.jpclett.9b00741 DOI Help

Authors: Natalie J. Tatum (Durham University) , Fernanda Duarte (University of Oxford) , Shina C. L. Kamerlin (Uppsala University) , Ehmke Pohl (University of Durham)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: The Journal Of Physical Chemistry Letters

State: Published (Approved)
Published: April 2019
Diamond Proposal Number(s): 18598

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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)