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

Hrast, Martina (author), Zdovc, Irena (author), Kočevar Glavač, Nina (author), Gobec, Stanislav (author), Frlan, Rok (author)

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.

• Language: English
• 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
• Year: 2023
• Number of pages: Str. 721-733
• Numbering: Vol. 37, iss. 12
• PID: 20.500.12556/RUL-152205
• UDC: 615.277.3
• ISSN on article: 0920-654X
• DOI: 10.1007/s10822-023-00535-z
• COBISS.SI-ID: 167509251
• Publication date in RUL: 10.11.2023

Record is a part of a journal

• Title: Journal of computer-aided molecular design
• Shortened title: J. comput.-aided mol. des.
• Publisher: Springer Nature
• ISSN: 0920-654X
• COBISS.SI-ID: 2621223

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• 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

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