Application of target repositioning and in silico screening to exploit fatty acid binding proteins (FABPs) from Echinoco
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Application of target repositioning and in silico screening to exploit fatty acid binding proteins (FABPs) from Echinococcus multilocularis as possible drug targets Julián A. Bélgamo1,3 · Lucas N. Alberca2,3 · Jorge L. Pórfido1,4 · Franco N. Caram Romero2 · Santiago Rodriguez1,3 · Alan Talevi2,3 · Betina Córsico1,3 · Gisela R. Franchini1,3 Received: 20 May 2020 / Accepted: 9 October 2020 © Springer Nature Switzerland AG 2020
Abstract 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. Keywords Drug repurposing · Target repurposing · FABP · Virtual screening · Echinococcus spp. · Neglected tropical diseases
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00352-8) contains supplementary material, which is available to authorized users. * Gisela R. Franchini [email protected] 1
Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), Facultad de Ciencias Médicas, Universidad Nacional de La Plata (UNLP)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), La Plata, Argentina
2
Laboratory of Bioactive Research and Development (LIDeB), Faculty of Exact Sciences, Universidad Nacional de La Plata (UNLP), Buenos Aires, Argentina
3
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
4
Present Address: Institut Pasteur Montevideo, Montevideo, Uruguay
Echinococcus multilocularis and Echinococcus granulosus are, respectively, the causative agents of alveolar and
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