Selective DNA gyrase inhibitors

multi-target in silico profiling with 3D-pharmacophores

Tihomir Tomašić (Author), Asta Zubrienė (Author), Žiga Skok (Author), Riccardo Martini (Author), Stane Pajk (Author), Izidor Sosič (Author), Janez Ilaš (Author), Daumantas Matulis (Author), Sharon D. Bryant (Author)

Abstract

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.

Keywords

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

Data

Language:	English
Year of publishing:	2021
Typology:	1.01 - Original Scientific Article
Organization:	UL FFA - Faculty of Pharmacy
UDC:	546.96:547.8
COBISS:	73095939
ISSN:	1424-8247
Views:	108
Downloads:	46
Average score:	0 (0 votes)
Metadata:

Other data

Secondary language:	Slovenian
Secondary keywords:	protibakterijsko delovanje;farmakoforni model;topoizomeraza II[alfa];tarčna aktivnost;zaviralci;Farmacevtska kemija;
Type (COBISS):	Article
Pages:	str. 1-24
Volume:	ǂVol. ǂ14
Issue:	ǂiss. ǂ8
Chronology:	2021
DOI:	10.3390/ph14080789
ID:	14947344