title: Exploring drug target flexibility using in situ click chemistry: application to a mycobacterial transcriptional regulator.
abstract: In situ click chemistry has been successfully applied to probe the ligand binding domain of EthR, a mycobacterial transcriptional regulator known to control the sensitivity of Mycobacterium tuberculosis to several antibiotics. Specific protein-templated ligands were generated in situ from one azide and six clusters of 10 acetylenic fragments. Comparative X-ray structures of EthR complexed with either clicked ligand BDM14950 or its azide precursor showed ligand-dependent conformational impacts on the protein architecture. This approach revealed two mobile phenylalanine residues that control the access to a previously hidden hydrophobic pocket that can be further exploited for the development of structurally diverse EthR inhibitors. This report shows that protein-directed in situ chemistry allows medicinal chemists to explore the conformational space of a ligand-binding pocket and is thus a valuable tool to guide drug design in the complex path of hit-to-lead processes.
authors: Nicolas
authors: N
authors: Willand
authors: Matthieu
authors: M
authors: Desroses
authors: Patrick
authors: P
authors: Toto
authors: Bertrand
authors: B
authors: Dirié
authors: Zoé
authors: Z
authors: Lens
authors: Vincent
authors: V
authors: Villeret
authors: Prakash
authors: P
authors: Rucktooa
authors: Camille
authors: C
authors: Locht
authors: Alain
authors: A
authors: Baulard
authors: Benoit
authors: B
authors: Deprez
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry* / Q000494:pharmacology; D001386:Azides / Q000737:chemistry* / Q000494:pharmacology; D057930:Click Chemistry / Q000379:methods*; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D008024:Ligands; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C559085:2-azido-1-(4-(3-thiophen-2-yl-(1,2,4)oxadiazol-5-yl)piperidin-1-yl)ethanone; D000995:Antitubercular Agents; D001386:Azides; C559084:BDM 31381; C481661:EthR protein, Mycobacterium tuberculosis; D008024:Ligands; D010069:Oxadiazoles; D012097:Repressor Proteins