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Título:
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Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen
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Autores:
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Cox, Jonathan A. G. ;
Mugumbate, Grace ;
Vela González del Peral, Laura ;
Jankute, Monika ;
A. Abrahams, Katherine ;
Jervis, Peter ;
Jackenkroll, Stefan ;
Pérez, Arancha ;
Alemparte, Carlos ;
Esquivias, Jorge ;
Lelièvre, Joël ;
Ramón Olayo, Fernando Antonio ;
Barros, David ;
Ballell, Lluis ;
S. Besra, Gurdyal
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Tipo de documento:
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texto impreso
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Editorial:
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Springer Nature, 2016
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Dimensiones:
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application/pdf
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Nota general:
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cc_by
info:eu-repo/semantics/openAccess
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Idiomas:
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Palabras clave:
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Estado = Publicado
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Materia = Ciencias Biomédicas: Biología
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Materia = Ciencias Biomédicas: Biología: Biología molecular
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Materia = Ciencias Biomédicas: Biología: Microbiología
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Tipo = Artículo
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Resumen:
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High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of ‘hit’ compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a ‘hit’ molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target.
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En línea:
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https://eprints.ucm.es/id/eprint/46387/1/Ramon.%20Novel%20inhibitors%20of%20Mycobacterium%20tuberculosis%20GuaB2.%202016.pdf
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