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

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2023-10-30 DOI:10.1016/j.bmc.2023.117466

Dalia M. Ahmed , David A.R. Sanders

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Abstract

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.

Abstract Image

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揭示靶向结核分枝杆菌UDP吡喃半乳糖突变酶的吡唑类化合物的意外聚集行为。

一种基于吡唑的化合物MS208先前被鉴定为结核分枝杆菌（MtUGM）UDP吡喃半乳糖突变酶的抑制剂。靶向这种酶是开发新型抗结核药物的一种新的治疗策略，因为MtUGM是细菌细胞壁合成的必需酶，而它在人类中不存在。有人提出MS208靶向MtUGM中的变构位点，因为MS208遵循混合抑制模型。MS208类似物DA10表现出竞争抑制而非混合抑制。在本文中，我们使用了一种综合的生物物理方法，包括热位移分析、动态光散射和核磁共振实验，以表明MS208和许多类似物对MtUGM表现出出乎意料的聚集行为。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.