RESUMO
A series of imidazo[1,2-a]indeno[1,2-e]pyrazin-4-ones that potently inhibit M. tuberculosis glutamine synthetase (GlnA1) has been identified by high throughput screening. Exploration of this series was performed owing to a short chemistry program. Despite possibly nanomolar inhibitions, none of these compounds was active on whole cell Mtb, suggesting that GlnA1 may not be a suitable target to find new anti-tubercular drugs.
Assuntos
Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , Glutamato-Amônia Ligase/antagonistas & inibidores , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Imidazóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Pirazinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glutamato-Amônia Ligase/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Ensaios de Triagem em Larga Escala , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Mycobacterium tuberculosis/enzimologia , Pirazinas/síntese química , Pirazinas/químicaRESUMO
We report the analysis of an in-house fragment screening campaign for the oncology target MEK1. The application of virtual screening (VS) as a primary fragment screening approach, followed by biophysical validation using differential screening fluorimetry (DSF), with resultant binding mode determination by X-ray crystallography (X-ray), is presented as the most time and cost-effective combination of in silico and in vitro methods to identify fragments. We demonstrate the effectiveness of the VS-DSF workflow for the early identification of fragments to both 'jump-start' the drug discovery project and to complement biochemical screening data.
