title: A structure-guided fragment-based approach for the discovery of allosteric inhibitors targeting the lipophilic binding site of transcription factor EthR.
abstract: 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.
authors: *Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors: Sachin
authors: S
authors: Surade
authors: †Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
authors: Nancy
authors: N
authors: Ty
authors: *Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors: Narin
authors: N
authors: Hengrung
authors: ‡Global Health Institute, Ecole Polytechnique Fédérale de Lausanne-EPFL, Lausanne, Switzerland.
authors: Benoit
authors: B
authors: Lechartier
authors: ‡Global Health Institute, Ecole Polytechnique Fédérale de Lausanne-EPFL, Lausanne, Switzerland.
authors: Stewart T
authors: ST
authors: Cole
authors: †Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
authors: Chris
authors: C
authors: Abell
authors: *Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, U.K.
authors: Tom L
authors: TL
authors: Blundell
mesh_terms: D000495:Allosteric Site / Q000502:physiology*; D001665:Binding Sites / Q000502:physiology; D018360:Crystallography, X-Ray; D016503:Drug Delivery Systems / Q000379:methods*; D055808:Drug Discovery / Q000379:methods*; D008055:Lipids; D009169:Mycobacterium tuberculosis; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000502:physiology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: C481661:EthR protein, Mycobacterium tuberculosis; D008055:Lipids; D010446:Peptide Fragments; D012097:Repressor Proteins; D014157:Transcription Factors