RESUMEN
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.
Asunto(s)
Antituberculosos/farmacología , Inhibidores Enzimáticos/farmacología , Glutamato-Amoníaco Ligasa/antagonistas & inhibidores , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Imidazoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Pirazinas/farmacología , Antituberculosos/síntesis química , Antituberculosos/química , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Glutamato-Amoníaco Ligasa/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/química , Ensayos Analíticos de Alto Rendimiento , Imidazoles/síntesis química , Imidazoles/química , Modelos Moleculares , Estructura Molecular , Mycobacterium tuberculosis/enzimología , Pirazinas/síntesis química , Pirazinas/químicaRESUMEN
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.