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

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

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.

• Jezik: Angleški jezik
• Ključne besede: MurF, quercitrin, myricetin, (–)-epicatechin, antibacterial activity
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo ; VF - Veterinarska fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2023
• Št. strani: Str. 721-733
• Številčenje: Vol. 37, iss. 12
• PID: 20.500.12556/RUL-152205
• UDK: 615.277.3
• ISSN pri članku: 0920-654X
• DOI: 10.1007/s10822-023-00535-z
• COBISS.SI-ID: 167509251
• Datum objave v RUL: 10.11.2023

Gradivo je del revije

• Naslov: Journal of computer-aided molecular design
• Skrajšan naslov: J. comput.-aided mol. des.
• Založnik: Springer Nature
• ISSN: 0920-654X
• COBISS.SI-ID: 2621223

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: MurF, kvercitrin, miricetin, (–)-epikatehin, antibakterijsko delovanje, farmacevtska kemija, tarčna zdravila