Application of target repositioning and in silico screening to exploit fatty acid binding proteins (FABPs) from Echinococcus multilocularis as possible drug targets
| Autor: | Alan Talevi, Jorge Luis Pórfido, Julián Alberto Bélgamo, Gisela Raquel Franchini, Lucas Nicolás Alberca, Santiago Rodríguez, Franco Nahuel Caram Romero, Betina Córsico |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Bioquímica
Virtual screening In silico Drug repurposing Computational biology Target repurposing Echinococcus multilocularis Fatty Acid-Binding Proteins 01 natural sciences Fatty acid-binding protein purl.org/becyt/ford/1 [https] Echinococcosis Echinococcus spp 0103 physical sciences Drug Discovery purl.org/becyt/ford/1.4 [https] Animals Computer Simulation Physical and Theoretical Chemistry Echinococcus granulosus Neglected tropical diseases Anthelmintics FABP 010304 chemical physics biology Drug Repositioning Helminth Proteins biology.organism_classification 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry Drug repositioning Echinococcus Pharmaceutical Preparations lipids (amino acids peptides and proteins) DrugBank |
| Zdroj: | SEDICI (UNLP) Universidad Nacional de La Plata instacron:UNLP CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| Popis: | Fatty acid binding proteins (FABPs) are small intracellular proteins that reversibly bind fatty acids and other hydrophobic ligands. In cestodes, due to their inability to synthesise fatty acids and cholesterol de novo, FABPs, together with other lipid binding proteins, have been proposed as essential, involved in the trafficking and delivery of such lipophilic metabolites. Pharmacological agents that modify specific parasite FABP function may provide control of lipid signalling pathways, inflammatory responses and metabolic regulation that could be of crucial importance for the parasite development and survival. Echinococcus multilocularis and Echinococcus granulosus are, respectively, the causative agents of alveolar and cystic echinococcosis (or hydatidosis). These diseases are included in the World Health Organization's list of priority neglected tropical diseases. Here, we explore the potential of FABPs from cestodes as drug targets. To this end, we have applied a target repurposing approach to identify novel inhibitors of Echinococcus spp. FABPs. An ensemble of computational models was developed and applied in a virtual screening campaign of DrugBank library. 21 hits belonging to the applicability domain of the ensemble models were identified, and 3 of the hits were assayed against purified E. multilocularis FABP, experimentally confirming the model's predictions. Noteworthy, this is to our best knowledge the first report on isolation and purification of such four FABP, for which initial structural and functional characterization is reported here. Instituto de Investigaciones Bioquímicas de La Plata Laboratorio de Investigación y Desarrollo de Bioactivos |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|