Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors. Issue 11 (6th November 2017)

• Record Type: Journal Article
• Authors: Bhusal, Ram Prasad; Patel, Krunal; Kwai, Brooke X. C.; Swartjes, Anne; Bashiri, Ghader; Reynisson, Jóhannes; Sperry, Jonathan; Leung, Ivanhoe K. H.
• Is Part Of: MedChemComm. Volume 8:Issue 11(2017)
• Page Start: 2155
• Page End: 2163
• Publication Date: 2017-11-06
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c7md00456g
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : The enzymes isocitrate lyase (ICL) isoforms 1 and 2 are essential for Mycobacterium tuberculosis survival within macrophages during latent tuberculosis (TB). Herein we report the development of a combined NMR spectroscopy and thermal shift assay for the screening and evaluation of ICL inhibitors. Abstract : The enzymes isocitrate lyase (ICL) isoforms 1 and 2 are essential for Mycobacterium tuberculosis survival within macrophages during latent tuberculosis (TB). As such, ICLs are attractive therapeutic targets for the treatment of tuberculosis. However, there are few biophysical assays that are available for accurate kinetic and inhibition studies of ICL in vitro . Herein we report the development of a combined NMR spectroscopy and thermal shift assay to study ICL inhibitors for both screening and inhibition constant (IC50 ) measurement. Operating this new assay in tandem with virtual high-throughput screening has led to the discovery of several new ICL1 inhibitors.