title: New applications for known drugs: Human glycogen synthase kinase 3 inhibitors as modulators of Aspergillus fumigatus growth.
abstract: Invasive aspergillosis (IA) is one of the most severe forms of fungi infection. IA disease is mainly due to Aspergillus fumigatus, an air-borne opportunistic pathogen. Mortality rate caused by IA is still very high (50-95%), because of difficulty in early diagnostics and reduced antifungal treatment options, thus new and efficient drugs are necessary. The aim of this work is, using Aspergillus nidulans as non-pathogen model, to develop efficient drugs to treat IA. The recent discovered role of glycogen synthase kinase-3 homologue, GskA, in A. fumigatus human infection and our previous experience on human GSK-3 inhibitors focus our attention on this kinase as a target for the development of antifungal drugs. With the aim to identify effective inhibitors of colonial growth of A. fumigatus we use A. nidulans as an accurate model for in vivo and in silico studies. Several well-known human GSK-3β inhibitors were tested for inhibition of A. nidulans colony growth. Computational tools as docking studies and binding site prediction was used to explain the different biological profile of the tested inhibitors. Three of the five tested hGSK3β inhibitors are able to reduce completely the colonial growth by covalent bind to the enzyme. Therefore these compounds may be useful in different applications to eradicate IA.
authors.affiliation: Centro de Investigaciones Biológicas (CIB, CSIC), Ramiro de Maeztu, 9, 28040 Madrid, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Sebastián-Pérez
authors.affiliation: Centro de Investigaciones Biológicas (CIB, CSIC), Ramiro de Maeztu, 9, 28040 Madrid, Spain.
authors.forename: Maria-Tsampika
authors.initials: MT
authors.lastname: Manoli
authors.affiliation: Centro de Investigaciones Biológicas (CIB, CSIC), Ramiro de Maeztu, 9, 28040 Madrid, Spain.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Pérez
authors.affiliation: Centro de Investigaciones Biológicas (CIB, CSIC), Ramiro de Maeztu, 9, 28040 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Madrid, Spain.
authors.forename: Emilia
authors.initials: E
authors.lastname: Mellado
authors.affiliation: Centro de Investigaciones Biológicas (CIB, CSIC), Ramiro de Maeztu, 9, 28040 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez
authors.affiliation: Centro de Investigaciones Biológicas (CIB, CSIC), Ramiro de Maeztu, 9, 28040 Madrid, Spain.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Espeso
authors.affiliation: Centro de Investigaciones Biológicas (CIB, CSIC), Ramiro de Maeztu, 9, 28040 Madrid, Spain. Electronic address: nuria.campillo@csic.es.
authors.forename: Nuria E
authors.initials: NE
authors.lastname: Campillo
mesh_terms: D000595:Amino Acid Sequence; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000254:growth & development*; D058492:Drug Repositioning; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3
keywords: Aspergillus fumigatus; Aspergillus nidulans; Docking; Fpocket; GSK-3 inhibitors