{"title":"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。","authors":"Dalia M. Ahmed , David A.R. Sanders","doi":"10.1016/j.bmc.2023.117466","DOIUrl":null,"url":null,"abstract":"<div><p>A pyrazole-based compound, <strong>MS208</strong><span>, was previously identified as an inhibitor of UDP-Galactopyranose Mutase from </span><span><em>Mycobacterium tuberculosis</em></span> (<em>Mt</em><span>UGM). Targeting this enzyme<span> is a novel therapeutic strategy for the development of new antituberculosis agents because </span></span><em>Mt</em><span>UGM is an essential enzyme for the bacterial cell wall synthesis and it is not present in human. It was proposed that </span><strong>MS208</strong><span> targets an allosteric site in </span><em>Mt</em>UGM as <strong>MS208</strong> followed a mixed inhibition model. <strong>DA10</strong>, an <strong>MS208</strong><span> 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 </span><strong>MS208</strong> and many analogues displayed unexpected aggregation behavior against <em>Mt</em>UGM.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117466"},"PeriodicalIF":3.3000,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Unraveling the unexpected aggregation behavior of Pyrazole-Based compounds Targeting Mycobacterium tuberculosis UDP-Galactopyranose mutase\",\"authors\":\"Dalia M. Ahmed , David A.R. Sanders\",\"doi\":\"10.1016/j.bmc.2023.117466\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>A pyrazole-based compound, <strong>MS208</strong><span>, was previously identified as an inhibitor of UDP-Galactopyranose Mutase from </span><span><em>Mycobacterium tuberculosis</em></span> (<em>Mt</em><span>UGM). Targeting this enzyme<span> is a novel therapeutic strategy for the development of new antituberculosis agents because </span></span><em>Mt</em><span>UGM is an essential enzyme for the bacterial cell wall synthesis and it is not present in human. It was proposed that </span><strong>MS208</strong><span> targets an allosteric site in </span><em>Mt</em>UGM as <strong>MS208</strong> followed a mixed inhibition model. <strong>DA10</strong>, an <strong>MS208</strong><span> 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 </span><strong>MS208</strong> and many analogues displayed unexpected aggregation behavior against <em>Mt</em>UGM.</p></div>\",\"PeriodicalId\":255,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry\",\"volume\":\"94 \",\"pages\":\"Article 117466\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2023-10-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0968089623003140\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089623003140","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Unraveling the unexpected aggregation behavior of Pyrazole-Based compounds Targeting Mycobacterium tuberculosis UDP-Galactopyranose mutase
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.
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.
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