ABSTRACT
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.
Subject(s)
Antitubercular Agents/pharmacology , Enzyme Inhibitors/pharmacology , Glutamate-Ammonia Ligase/antagonists & inhibitors , Heterocyclic Compounds, 4 or More Rings/pharmacology , Imidazoles/pharmacology , Mycobacterium tuberculosis/drug effects , Pyrazines/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glutamate-Ammonia Ligase/metabolism , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , High-Throughput Screening Assays , Imidazoles/chemical synthesis , Imidazoles/chemistry , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/enzymology , Pyrazines/chemical synthesis , Pyrazines/chemistryABSTRACT
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.
