Mycobacterial dihydrofolate reductase inhibitors identified using chemogenomic methods and in vitro validation.
PLoS One
; 10(3): e0121492, 2015.
Article
em En
| MEDLINE
| ID: mdl-25799414
ABSTRACT
The lack of success in target-based screening approaches to the discovery of antibacterial agents has led to reemergence of phenotypic screening as a successful approach of identifying bioactive, antibacterial compounds. A challenge though with this route is then to identify the molecular target(s) and mechanism of action of the hits. This target identification, or deorphanization step, is often essential in further optimization and validation studies. Direct experimental identification of the molecular target of a screening hit is often complex, precisely because the properties and specificity of the hit are not yet optimized against that target, and so many false positives are often obtained. An alternative is to use computational, predictive, approaches to hypothesize a mechanism of action, which can then be validated in a more directed and efficient manner. Specifically here we present experimental validation of an in silico prediction from a large-scale screen performed against Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis. The two potent anti-tubercular compounds studied in this case, belonging to the tetrahydro-1,3,5-triazin-2-amine (THT) family, were predicted and confirmed to be an inhibitor of dihydrofolate reductase (DHFR), a known essential Mtb gene, and already clinically validated as a drug target. Given the large number of similar screening data sets shared amongst the community, this in vitro validation of these target predictions gives weight to computational approaches to establish the mechanism of action (MoA) of novel screening hit.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tetra-Hidrofolato Desidrogenase
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Genômica
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Avaliação Pré-Clínica de Medicamentos
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Antagonistas do Ácido Fólico
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Mycobacterium tuberculosis
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
PLoS One
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Reino Unido