Exploring drug target flexibility using in situ click chemistry: application to a mycobacterial transcriptional regulator.
ACS Chem Biol
; 5(11): 1007-13, 2010 Nov 19.
Article
em En
| MEDLINE
| ID: mdl-20704273
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oxidiazóis
/
Proteínas Repressoras
/
Azidas
/
Química Click
/
Mycobacterium tuberculosis
/
Antituberculosos
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article