Unraveling the unexpected aggregation behavior of Pyrazole-Based compounds Targeting Mycobacterium tuberculosis UDP-Galactopyranose mutase

[Display omitted] A pyrazole-based compound, MS208, was previously identified as an inhibitor of UDP-Galactopyranose Mutase from Mycobacterium tuberculosis (MtUGM). Targeting this enzyme is a novel therapeutic strategy for the development of new antituberculosis agents because MtUGM is an essential...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2023-10, Vol.94, p.117466-117466, Article 117466
Main Authors: Ahmed, Dalia M., Sanders, David A.R.
Format: Article
Language:English
Subjects:
Aggregation
Antituberculosis
Inhibitors
Pyrazole
UDP-galactopyranose mutase
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Summary:[Display omitted] A pyrazole-based compound, MS208, was previously identified as an inhibitor of UDP-Galactopyranose Mutase from Mycobacterium tuberculosis (MtUGM). Targeting this enzyme is a novel therapeutic strategy for the development of new antituberculosis agents because MtUGM is an essential enzyme for the bacterial cell wall synthesis and it is not present in human. It was proposed that MS208 targets an allosteric site in MtUGM as MS208 followed a mixed inhibition model. DA10, an MS208 analogue, showed competitive inhibition rather than mixed inhibition. In this paper, we have used an integrated biophysical approach, including thermal shift assays, dynamic light scattering and nuclear magnetic resonance experiments, to show that MS208 and many analogues displayed unexpected aggregation behavior against MtUGM.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2023.117466