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

Povzetek

Background: 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. (2) Methods: To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase II[alpha] (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. (3) Results: 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. (4) Conclusions: 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.

Ključne besede

antibacterial;ATP-competitive;DNA gyrase;Hsp90;pharmacophore model;topoisomerase II[alpha];target activity profiling;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 546.96:547.8
COBISS: 73095939 Povezava se bo odprla v novem oknu
ISSN: 1424-8247
Št. ogledov: 108
Št. prenosov: 46
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: protibakterijsko delovanje;farmakoforni model;topoizomeraza II[alfa];tarčna aktivnost;zaviralci;Farmacevtska kemija;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-24
Letnik: ǂVol. ǂ14
Zvezek: ǂiss. ǂ8
Čas izdaje: 2021
DOI: 10.3390/ph14080789
ID: 14947344