20.500.12556/RUL-135975 Selective DNA gyrase inhibitors multi-target in silico profiling with 3D-pharmacophores 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. antibacterial ATP-competitive DNA gyrase Hsp90 pharmacophore model topoisomerase II target activity profiling topoisomerase IIα protibakterijsko delovanje farmakoforni model topoizomeraza IIα tarčna aktivnost zaviralci farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2022-04-05 11:49:30 2022-04-05 11:49:35 2022-09-15 04:13:02 0000-00-00 00:00:00 2021 0 0 24 str. iss. 8, art. 789 Vol. 14 2021 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 546.96:547.8 1424-8247 10.3390/ph14080789 73095939 RAZ_Tomasic_Tihomir_2021.pdf RAZ_Tomasic_Tihomir_2021.pdf 1 42D4C98F97AD2A18F3261BF6EAA8618E 4567994211eeecc6194075561bcabfb785cab45c887f483f89176de11904c68c e8e21900-b4c5-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155322 https://www.mdpi.com/1424-8247/14/8/789 1 abc5bf88-b4c5-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=155321 Fakulteta za farmacijo 0 0 0