Mur ligase F as a new target for the flavonoids quercitrin, myricetin, and (–)-epicatechin
ID Hrast, Martina (Author), ID Zdovc, Irena (Author), ID Kočevar Glavač, Nina (Author), ID Gobec, Stanislav (Author), ID Frlan, Rok (Author)

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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 IC$_{50}$ 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.

Keywords:MurF, quercitrin, myricetin, (–)-epicatechin, antibacterial activity
Work type:Article
Typology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
VF - Veterinary Faculty
Publication status:Published
Publication version:Version of Record
Number of pages:Str. 721-733
Numbering:Vol. 37, iss. 12
PID:20.500.12556/RUL-152205 This link opens in a new window
ISSN on article:0920-654X
DOI:10.1007/s10822-023-00535-z This link opens in a new window
COBISS.SI-ID:167509251 This link opens in a new window
Publication date in RUL:10.11.2023
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Record is a part of a journal

Title:Journal of computer-aided molecular design
Shortened title:J. comput.-aided mol. des.
Publisher:Springer Nature
COBISS.SI-ID:2621223 This link opens in a new window


License:CC BY 4.0, Creative Commons Attribution 4.0 International
Description:This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

Keywords:MurF, kvercitrin, miricetin, (–)-epikatehin, antibakterijsko delovanje, farmacevtska kemija, tarčna zdravila


Funder:ARRS - Slovenian Research Agency
Project number:J1-2484
Name:Razvoj protibakterijskih učinkovin z delovanjem na validirane tarče v biosintezi peptidoglikana

Funder:ARRS - Slovenian Research Agency
Project number:P1-0208
Name:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Funder:ARRS - Slovenian Research Agency
Project number:P4-0092
Name:Zdravje živali, okolje in varna hrana

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