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https://cris.library.msu.ac.zw//handle/11408/4905
Title: | Novel inhibitors of Mycobacterium tuberculosis GuaB2 identified by a target based high-throughput phenotypic screen | Authors: | Cox, Jonathan A G Mugumbate, Grace Peral, Laura Vela-Glez Del Jankute, Monika Abrahams, Katherine A Jervis, Peter Jackenkroll, Stefan Perez, Arancha Alemparte, Carlos Esquivias, Jorge Lelièvre, Joël Ramon, Fernando Barros, David Ballell, Lluis Besra, Gurdyal S |
Keywords: | Antibiotics High-throughput screening Phenotypic screening Target validation |
Issue Date: | 2016 | Publisher: | Nature Research | Series/Report no.: | Scientific reports;Vol. 6,No. 38986 | Abstract: | High-throughput phenotypic screens have re-emerged as screening tools in antibiotic discovery. The advent of such technologies has rapidly accelerated the identification of 'hit' compounds. A pre-requisite to medicinal chemistry optimisation programmes required to improve the drug-like properties of a 'hit' molecule is identification of its mode of action. Herein, we have combined phenotypic screening with a biased target-specific screen. The inosine monophosphate dehydrogenase (IMPDH) protein GuaB2 has been identified as a drugable target in Mycobacterium tuberculosis, however previously identified compounds lack the desired characteristics necessary for further development into lead-like molecules. This study has identified 7 new chemical series from a high-throughput resistance-based phenotypic screen using Mycobacterium bovis BCG over-expressing GuaB2. Hit compounds were identified in a single shot high-throughput screen, validated by dose response and subjected to further biochemical analysis. The compounds were also assessed using molecular docking experiments, providing a platform for their further optimisation using medicinal chemistry. This work demonstrates the versatility and potential of GuaB2 as an anti-tubercular drug target. | URI: | https://www.nature.com/articles/srep38986 http://hdl.handle.net/11408/4905 |
ISSN: | 2045-2322 |
Appears in Collections: | Research Papers |
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File | Description | Size | Format | |
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Novel inhibitors. pdf.pdf | Full Text.pdf | 3.36 MB | Adobe PDF | View/Open |
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