Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors

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 availab...

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Autores principales: Bhusal, Ram Prasad, Patel, Krunal, Kwai, Brooke X. C., Swartjes, Anne, Bashiri, Ghader, Reynisson, Jóhannes, Sperry, Jonathan, Leung, Ivanhoe K. H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2017
Materias:
Chemistry
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072051/
https://www.ncbi.nlm.nih.gov/pubmed/30108733
http://dx.doi.org/10.1039/c7md00456g
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author Bhusal, Ram Prasad
Patel, Krunal
Kwai, Brooke X. C.
Swartjes, Anne
Bashiri, Ghader
Reynisson, Jóhannes
Sperry, Jonathan
Leung, Ivanhoe K. H.
author_facet Bhusal, Ram Prasad
Patel, Krunal
Kwai, Brooke X. C.
Swartjes, Anne
Bashiri, Ghader
Reynisson, Jóhannes
Sperry, Jonathan
Leung, Ivanhoe K. H.
author_sort Bhusal, Ram Prasad
collection PubMed
description 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 (IC(50)) measurement. Operating this new assay in tandem with virtual high-throughput screening has led to the discovery of several new ICL1 inhibitors.
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spelling pubmed-60720512018-10-17 Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors Bhusal, Ram Prasad Patel, Krunal Kwai, Brooke X. C. Swartjes, Anne Bashiri, Ghader Reynisson, Jóhannes Sperry, Jonathan Leung, Ivanhoe K. H. Medchemcomm Chemistry 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 (IC(50)) measurement. Operating this new assay in tandem with virtual high-throughput screening has led to the discovery of several new ICL1 inhibitors. Royal Society of Chemistry 2017-10-17 /pmc/articles/PMC6072051/ /pubmed/30108733 http://dx.doi.org/10.1039/c7md00456g Text en This journal is © The Royal Society of Chemistry 2017 http://creativecommons.org/licenses/by-nc/3.0/ This article is freely available. This article is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported Licence (CC BY-NC 3.0)
spellingShingle Chemistry
Bhusal, Ram Prasad
Patel, Krunal
Kwai, Brooke X. C.
Swartjes, Anne
Bashiri, Ghader
Reynisson, Jóhannes
Sperry, Jonathan
Leung, Ivanhoe K. H.
Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors
title Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors
title_full Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors
title_fullStr Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors
title_full_unstemmed Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors
title_short Development of NMR and thermal shift assays for the evaluation of Mycobacterium tuberculosis isocitrate lyase inhibitors
title_sort development of nmr and thermal shift assays for the evaluation of mycobacterium tuberculosis isocitrate lyase inhibitors
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072051/
https://www.ncbi.nlm.nih.gov/pubmed/30108733
http://dx.doi.org/10.1039/c7md00456g
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