{"title":"天然代谢物熊果酸作为结核分枝杆菌休眠调节剂 DosR 的抑制剂：分子对接、分子动力学模拟和自由能分析的证据。","authors":"Babban Jee, Prem Prakash Sharma, Vijay Kumar Goel, Sanjay Kumar, Yogesh Singh, Brijesh Rathi","doi":"10.2174/1573409919666230201100543","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>DosR is a transcriptional regulator of Mycobacterium tuberculosis</i> (MTB), governing the expression of a set of nearly 50 genes that is often referred to as 'dormancy regulon'. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB.</p><p><strong>Objective: </strong>We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico</i> approaches.</p><p><strong>Methods: </strong>The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB.</p><p><strong>Results: </strong>Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature.</p><p><strong>Conclusion: </strong>The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 6","pages":"425-437"},"PeriodicalIF":1.5000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Natural Metabolite Ursolic Acid as an Inhibitor of Dormancy Regulator DosR of <i>Mycobacterium tuberculosis</i>: Evidence from Molecular Docking, Molecular Dynamics Simulation and Free Energy Analysis.\",\"authors\":\"Babban Jee, Prem Prakash Sharma, Vijay Kumar Goel, Sanjay Kumar, Yogesh Singh, Brijesh Rathi\",\"doi\":\"10.2174/1573409919666230201100543\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>DosR is a transcriptional regulator of Mycobacterium tuberculosis</i> (MTB), governing the expression of a set of nearly 50 genes that is often referred to as 'dormancy regulon'. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB.</p><p><strong>Objective: </strong>We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico</i> approaches.</p><p><strong>Methods: </strong>The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB.</p><p><strong>Results: </strong>Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature.</p><p><strong>Conclusion: </strong>The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.</p>\",\"PeriodicalId\":10886,\"journal\":{\"name\":\"Current computer-aided drug design\",\"volume\":\"19 6\",\"pages\":\"425-437\"},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Current computer-aided drug design\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2174/1573409919666230201100543\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current computer-aided drug design","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2174/1573409919666230201100543","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Natural Metabolite Ursolic Acid as an Inhibitor of Dormancy Regulator DosR of Mycobacterium tuberculosis: Evidence from Molecular Docking, Molecular Dynamics Simulation and Free Energy Analysis.
Background: DosR is a transcriptional regulator of Mycobacterium tuberculosis (MTB), governing the expression of a set of nearly 50 genes that is often referred to as 'dormancy regulon'. The inhibition of DosR expression by an appropriate inhibitor may be a crucial step against MTB.
Objective: We targeted the DosR with natural metabolites, ursolic acid (UA) and carvacrol (CV), using in silico approaches.
Methods: The molecular docking, molecular dynamics (MD) simulation for 200 ns, calculation of binding energies by MM-GBSA method, and ADMET calculation were performed to evaluate the inhibitory potential of natural metabolites ursolic acid (UA) and carvacrol (CV) against DosR of MTB.
Results: Our study demonstrated that UA displayed significant compatibility with DosR during the 200 ns timeframe of MD simulation. The thermodynamic binding energies by MM-GBSA also suggested UA conformational stability within the binding pocket. The SwissADME, pkCSM, and OSIRIS DataWarrior showed a drug-likeness profile of UA, where Lipinski profile was satisfied with one violation (MogP > 4.15) with no toxicities, no mutagenicity, no reproductive effect, and no irritant nature.
Conclusion: The present study suggests that UA has the potency to inhibit the DosR expression and warrants further investigation on harnessing its clinical potential.
期刊介绍：
Aims & Scope
Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design.
Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews, original research articles and letter articles written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, theoretical chemistry; computational chemistry; computer and molecular graphics; molecular modeling; protein engineering; drug design; expert systems; general structure-property relationships; molecular dynamics; chemical database development and usage etc., providing excellent rationales for drug development.
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