| Autor: |
Bedoya-Cardona JE; Facultad de Ciencias Básicas, Universidad de Medellín, Medellin 050026, Colombia., Rubio-Carrasquilla M; Facultad de Ciencias Básicas, Universidad de Medellín, Medellin 050026, Colombia.; Corporación para Investigaciones Biológicas, Medellin 050034, Colombia., Ramírez-Velásquez IM; Facultad de Ciencias Básicas, Universidad de Medellín, Medellin 050026, Colombia.; Instituto Tecnológico Metropolitano, Medellin 050034, Colombia., Valdés-Tresanco MS; Facultad de Ciencias Básicas, Universidad de Medellín, Medellin 050026, Colombia., Moreno E; Facultad de Ciencias Básicas, Universidad de Medellín, Medellin 050026, Colombia. |
| Jazyk: |
angličtina |
| Zdroj: |
Molecules (Basel, Switzerland) [Molecules] 2023 Jan 10; Vol. 28 (2). Date of Electronic Publication: 2023 Jan 10. |
| DOI: |
10.3390/molecules28020692 |
| Abstrakt: |
Invasive fungal infections represent a public health problem that worsens over the years with the increasing resistance to current antimycotic agents. Therefore, there is a compelling medical need of widening the antifungal drug repertoire, following different methods such as drug repositioning, identification and validation of new molecular targets and developing new inhibitors against these targets. In this work we developed a structure-based strategy for drug repositioning and new drug design, which can be applied to infectious fungi and other pathogens. Instead of applying the commonly accepted off-target criterion to discard fungal proteins with close homologues in humans, the core of our approach consists in identifying fungal proteins with active sites that are structurally similar, but preferably not identical to binding sites of proteins from the so-called "human pharmacolome". Using structural information from thousands of human protein target-inhibitor complexes, we identified dozens of proteins in fungal species of the genera Histoplasma , Candida , Cryptococcus , Aspergillus and Fusarium , which might be exploited for drug repositioning and, more importantly, also for the design of new fungus-specific inhibitors. As a case study, we present the in vitro experiments performed with a set of selected inhibitors of the human mitogen-activated protein kinases 1/2 (MEK1/2), several of which showed a marked cytotoxic activity in different fungal species. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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