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.

IF 1.5 4区医学 Q4 CHEMISTRY, MEDICINAL Current computer-aided drug design Pub Date : 2023-01-01 DOI:10.2174/1573409919666230201100543

Babban Jee, Prem Prakash Sharma, Vijay Kumar Goel, Sanjay Kumar, Yogesh Singh, Brijesh Rathi

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Abstract

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.

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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。

背景：DosR是结核分枝杆菌（MTB）的转录调节因子，控制着近50个基因的表达，这些基因通常被称为 "休眠调节子"。通过适当的抑制剂抑制 DosR 的表达可能是抗击 MTB 的关键一步：目的：我们利用硅学方法，以天然代谢物熊果酸（UA）和香芹酚（CV）作为 DosR 的靶标：方法：通过分子对接、200 ns 的分子动力学（MD）模拟、MM-GBSA 方法计算结合能以及 ADMET 计算，评估天然代谢物熊果酸（UA）和香芹酚（CV）对 MTB DosR 的抑制潜力：我们的研究表明，在 MD 模拟的 200 ns 时间范围内，UA 与 DosR 的相容性很好。MM-GBSA 的热力学结合能也表明 UA 在结合袋中的构象具有稳定性。SwissADME、pkCSM和OSIRIS DataWarrior显示了UA的药物相似性特征，其中Lipinski特征满足一次违规（MogP > 4.15），无毒性、无致突变性、无生殖影响和无刺激性：本研究表明，UA 具有抑制 DosR 表达的效力，值得进一步研究其临床潜力。

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

Current computer-aided drug design 医学-计算机：跨学科应用

CiteScore

3.70

自引率

5.90%

发文量

审稿时长

>12 weeks

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.