{"title":"靶向十戊烯基磷酸基-β- d -核糖氧化酶(DprE1)的新型支架化学抑制剂的鉴定","authors":"Tatsuki Matsunaga, Kohei Monobe, Shunsuke Aoki","doi":"10.2174/1871526523666230309110705","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Tuberculosis is the second leading cause of death from infectious diseases worldwide. Multidrug-resistant Mycobacterium tuberculosis is spreading throughout the world, creating a crisis. Hence, there is a need to develop anti-tuberculosis drugs with novel structures and versatile mechanisms of action.</p><p><strong>Objective: </strong>In this study, we identified antimicrobial compounds with a novel skeleton that inhibits mycobacterium decaprenylphosphoryl-β-D-ribose oxidase (DprE1).</p><p><strong>Methods: </strong>A multi-step, in silico, structure-based drug screening identified potential DprE1 inhibitors from a library of 154,118 compounds. We experimentally verified the growth inhibitory effects of the eight selected candidate compounds against Mycobacterium smegmatis. Molecular dynamics simulations were performed to understand the mechanism of molecular interactions between DprE1 and ompound 4.</p><p><strong>Results: </strong>Eight compounds were selected through in silico screening. Compound 4 showed strong growth inhibition against M. smegmatis. Molecular dynamics simulation (50 ns) predicted direct and stable binding of Compound 4 to the active site of DprE1.</p><p><strong>Conclusion: </strong>The structural analysis of the novel scaffold in Compound 4 can pave way for antituberculosis drug development and discovery.</p>","PeriodicalId":13678,"journal":{"name":"Infectious disorders drug targets","volume":"23 5","pages":"e090323214508"},"PeriodicalIF":0.0000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Identification of a Chemical Inhibitor with a Novel Scaffold Targeting Decaprenylphosphoryl-β-D-Ribose Oxidase (DprE1).\",\"authors\":\"Tatsuki Matsunaga, Kohei Monobe, Shunsuke Aoki\",\"doi\":\"10.2174/1871526523666230309110705\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Tuberculosis is the second leading cause of death from infectious diseases worldwide. Multidrug-resistant Mycobacterium tuberculosis is spreading throughout the world, creating a crisis. Hence, there is a need to develop anti-tuberculosis drugs with novel structures and versatile mechanisms of action.</p><p><strong>Objective: </strong>In this study, we identified antimicrobial compounds with a novel skeleton that inhibits mycobacterium decaprenylphosphoryl-β-D-ribose oxidase (DprE1).</p><p><strong>Methods: </strong>A multi-step, in silico, structure-based drug screening identified potential DprE1 inhibitors from a library of 154,118 compounds. We experimentally verified the growth inhibitory effects of the eight selected candidate compounds against Mycobacterium smegmatis. Molecular dynamics simulations were performed to understand the mechanism of molecular interactions between DprE1 and ompound 4.</p><p><strong>Results: </strong>Eight compounds were selected through in silico screening. Compound 4 showed strong growth inhibition against M. smegmatis. Molecular dynamics simulation (50 ns) predicted direct and stable binding of Compound 4 to the active site of DprE1.</p><p><strong>Conclusion: </strong>The structural analysis of the novel scaffold in Compound 4 can pave way for antituberculosis drug development and discovery.</p>\",\"PeriodicalId\":13678,\"journal\":{\"name\":\"Infectious disorders drug targets\",\"volume\":\"23 5\",\"pages\":\"e090323214508\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Infectious disorders drug targets\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.2174/1871526523666230309110705\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"Pharmacology, Toxicology and Pharmaceutics\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Infectious disorders drug targets","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2174/1871526523666230309110705","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Pharmacology, Toxicology and Pharmaceutics","Score":null,"Total":0}
引用次数: 0
摘要
背景:结核病是全球第二大传染病致死原因。耐多药结核分枝杆菌正在全世界蔓延，造成了一场危机。因此，有必要开发具有新型结构和多种作用机制的抗结核药物。目的:在本研究中，我们鉴定了具有抑制分枝杆菌十烯丙基磷酸基-β- d -核糖氧化酶(DprE1)的新型骨架的抗菌化合物。方法:通过多步骤、基于计算机结构的药物筛选，从一个包含154,118个化合物的文库中鉴定出潜在的DprE1抑制剂。实验验证了8种候选化合物对耻垢分枝杆菌的生长抑制作用。通过分子动力学模拟了解DprE1与化合物4分子相互作用的机理。结果:通过硅筛选筛选出8个化合物。化合物4对耻垢分枝杆菌有较强的生长抑制作用。分子动力学模拟(50 ns)预测了化合物4与DprE1活性位点的直接稳定结合。结论:化合物4中新型支架的结构分析可为抗结核药物的开发和发现铺平道路。
Identification of a Chemical Inhibitor with a Novel Scaffold Targeting Decaprenylphosphoryl-β-D-Ribose Oxidase (DprE1).
Background: Tuberculosis is the second leading cause of death from infectious diseases worldwide. Multidrug-resistant Mycobacterium tuberculosis is spreading throughout the world, creating a crisis. Hence, there is a need to develop anti-tuberculosis drugs with novel structures and versatile mechanisms of action.
Objective: In this study, we identified antimicrobial compounds with a novel skeleton that inhibits mycobacterium decaprenylphosphoryl-β-D-ribose oxidase (DprE1).
Methods: A multi-step, in silico, structure-based drug screening identified potential DprE1 inhibitors from a library of 154,118 compounds. We experimentally verified the growth inhibitory effects of the eight selected candidate compounds against Mycobacterium smegmatis. Molecular dynamics simulations were performed to understand the mechanism of molecular interactions between DprE1 and ompound 4.
Results: Eight compounds were selected through in silico screening. Compound 4 showed strong growth inhibition against M. smegmatis. Molecular dynamics simulation (50 ns) predicted direct and stable binding of Compound 4 to the active site of DprE1.
Conclusion: The structural analysis of the novel scaffold in Compound 4 can pave way for antituberculosis drug development and discovery.
期刊介绍：
Infectious Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in infectious disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal contains a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in infectious disorders. As the discovery, identification, characterization and validation of novel human drug targets for anti-infective drug discovery continues to grow, this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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