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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.

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Amines Q 0120Synthesis of N-(Iodophenyl)-amides via an Unprecedented Ullmann-Finkelstein Tandem Reaction. -The conversion is highly efficient under conditions A). -(TOTO, P.; GESQUIERE, J.-C.; DEPREZ, B.; WILLAND*, N.; Tetrahedron Lett. 47 (2006) 7, 1181-1186; Lab. Chim. Org., Fac. Sci. Pharm. Biol., F-59006 Lille, Fr.; Eng.) -Mais 21-076