Mur ligase F as a new target for the flavonoids quercitrin, myricetin, and (–)-epicatechin

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Martina Hrast Rambaher, Irena Zdovc, Nina Kočevar Glavač, Stanislav Gobec, Rok Frlan
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Abstract

MurC, D, E, and F are ATP-dependent ligases involved in the stepwise assembly of the tetrapeptide stem of forming peptidoglycan. As highly conserved targets found exclusively in bacterial cells, they are of significant interest for antibacterial drug discovery. In this study, we employed a computer-aided molecular design approach to identify potential inhibitors of MurF. A biochemical inhibition assay was conducted, screening twenty-four flavonoids and related compounds against MurC-F, resulting in the identification of quercitrin, myricetin, and (–)-epicatechin as MurF inhibitors with IC50 values of 143 µM, 139 µM, and 92 µM, respectively. Notably, (–)-epicatechin demonstrated mixed type inhibition with ATP and uncompetitive inhibition with d-Ala-d-Ala dipeptide and UM3DAP substrates. Furthermore, in silico analysis using Sitemap and subsequent docking analysis using Glide revealed two plausible binding sites for (–)-epicatechin. The study also investigated the crucial structural features required for activity, with a particular focus on the substitution pattern and hydroxyl group positions, which were found to be important for the activity. The study highlights the significance of computational approaches in targeting essential enzymes involved in bacterial peptidoglycan synthesis.

Graphical abstract

Abstract Image

Abstract Image

Abstract Image

Mur连接酶F作为黄酮类化合物槲皮素、杨梅素和(-)-表儿茶素的新靶点。
MurC、D、E和F是ATP依赖性连接酶,参与形成肽聚糖的四肽茎的逐步组装。作为仅在细菌细胞中发现的高度保守的靶标,它们对抗菌药物的发现具有重要意义。在这项研究中,我们采用计算机辅助分子设计方法来识别MurF的潜在抑制剂。进行了生物化学抑制试验,筛选了24种黄酮类化合物和相关化合物对抗MurC-F,从而鉴定出槲皮素、杨梅素和(-)-表儿茶素为MurF抑制剂,IC50值分别为143µM、139µM和92µM。值得注意的是,(-)-表儿茶素与ATP表现出混合型抑制作用,与D-Ala-D-Ala二肽和UM3DAP底物表现出非竞争性抑制作用。此外,使用Sitemap的计算机分析和随后使用Glide的对接分析揭示了(-)-表儿茶素的两个可能的结合位点。该研究还研究了活性所需的关键结构特征,特别关注取代模式和羟基位置,这些对活性很重要。该研究强调了计算方法在靶向参与细菌肽聚糖合成的必需酶方面的重要性。
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
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - 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.
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