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Selective DNA gyrase inhibitors : multi-target in silico profiling with 3D-pharmacophores
ID Tomašič, Tihomir (Avtor), ID Zubrienė, Asta (Avtor), ID Skok, Žiga (Avtor), ID Martini, Riccardo (Avtor), ID Pajk, Stane (Avtor), ID Sosič, Izidor (Avtor), ID Ilaš, Janez (Avtor), ID Matulis, Daumantas (Avtor), ID Bryant, Sharon D. (Avtor)

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Izvleček
DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors against closely related human ATP-binding enzymes should be evaluated early in development to avoid off-target binding to homologous binding domains. To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase IIα (TopoII), and the Hsp90 N-terminal domain (NTD) to be used in in silico activity profiling paradigms to identify molecules selective for GyrB over TopoII and Hsp90, as starting points for hit expansion and lead optimization. The models were used to profile highly active GyrB, TopoII, and Hsp90 inhibitors. Selected compounds were tested in in vitro assays. GyrB inhibitors 1 and 2 were inactive against TopoII and Hsp90, while 3 and 4, potent Hsp90 inhibitors, displayed no inhibition of GyrB and TopoII, and TopoII inhibitors 5 and 6 were inactive at GyrB and Hsp90. The results provide a proof of concept for the use of target activity profiling methods to identify selective starting points for hit and lead identification.

Jezik:Angleški jezik
Ključne besede:antibacterial, ATP-competitive, DNA gyrase, Hsp90, pharmacophore model, topoisomerase II, target activity profiling, topoisomerase IIα
Vrsta gradiva:Članek v reviji
Tipologija:1.01 - Izvirni znanstveni članek
Organizacija:FFA - Fakulteta za farmacijo
Status publikacije:Objavljeno
Različica publikacije:Objavljena publikacija
Leto izida:2021
Št. strani:24 str.
Številčenje:Vol. 14, iss. 8, art. 789
PID:20.500.12556/RUL-135975 Povezava se odpre v novem oknu
UDK:546.96:547.8
ISSN pri članku:1424-8247
DOI:10.3390/ph14080789 Povezava se odpre v novem oknu
COBISS.SI-ID:73095939 Povezava se odpre v novem oknu
Datum objave v RUL:05.04.2022
Število ogledov:8350
Število prenosov:181
Metapodatki:XML DC-XML DC-RDF
:
TOMAŠIČ, Tihomir, ZUBRIENĖ, Asta, SKOK, Žiga, MARTINI, Riccardo, PAJK, Stane, SOSIČ, Izidor, ILAŠ, Janez, MATULIS, Daumantas in BRYANT, Sharon D., 2021, Selective DNA gyrase inhibitors : multi-target in silico profiling with 3D-pharmacophores. Pharmaceuticals [na spletu]. 2021. Vol. 14, no. 8,  789. [Dostopano 6 julij 2025]. DOI 10.3390/ph14080789. Pridobljeno s: https://repozitorij.uni-lj.si/IzpisGradiva.php?lang=slv&id=135975
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Gradivo je del revije

Naslov:Pharmaceuticals
Skrajšan naslov:Pharmaceuticals
Založnik:MDPI
ISSN:1424-8247
COBISS.SI-ID:517582617 Povezava se odpre v novem oknu

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.
Začetek licenciranja:10.08.2021

Sekundarni jezik

Jezik:Slovenski jezik
Ključne besede:protibakterijsko delovanje, farmakoforni model, topoizomeraza IIα, tarčna aktivnost, zaviralci, farmacevtska kemija

Projekti

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:P1-0208
Naslov:Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:J1-1717
Naslov:Razvoj novih zaviralcev Hsp90 s protitumornim delovanjem

Financer:ARRS - Agencija za raziskovalno dejavnost Republike Slovenije
Številka projekta:BI-LT/20-22-009

Financer:Drugi - Drug financer ali več financerjev
Program financ.:COST
Številka projekta:CA15135

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