A structure-guided fragment-based approach for the discovery of allosteric inhibitors targeting the lipophilic binding site of transcription factor EthR

• DOI: 10.1042/bj20131127
• Publication Date: 2013-12-09T14:46:32Z
• Authors: Sachin Surade; Nancy Ty; Narin Hengrung; Benoit Lechartier; Stewart T. Cole; Chris Abell; Tom L. Blundell
• Keywords: 0301 basic medicine; Binding Sites; fragment screening; Mycobacterium tuberculosis; fragment linking; Crystallography, X-Ray; Lipids; Peptide Fragments; Protein Structure, Secondary; Protein Structure, Tertiary; 3. Good health; Repressor Proteins; EthR; Structure-Activity Relationship; 03 medical and health sciences; Drug Delivery Systems; tuberculosis; Drug Discovery; Allosteric Site; Transcription Factors

A structure-guided fragment-based approach was used to target the lipophilic allosteric binding site of Mycobacterium tuberculosis EthR. This elongated channel has many hydrophobic residues lining the binding site, with few opportunities for hydrogen bonding. We demonstrate that a fragment-based approach involving the inclusion of flexible fragments in the library leads to an efficient exploration of chemical space, that fragment binding can lead to an extension of the cavity, and that fragments are able to identify hydrogen-bonding opportunities in this hydrophobic environment that are not exploited in Nature. In the present paper, we report the identification of a 1 μM affinity ligand obtained by structure-guided fragment linking.