Application of target repositioning and in silico screening to exploit fatty acid binding proteins (FABPs) from Echinococcus multilocularis as possible drug targets

BELGAMO JULIAN A.; ALBERCA LUCAS N.; PÓRFIDO JORGE L.; CARAM ROMERO FRANCO N.; RODRÍGUEZ SANTIAGO; TALEVI ALAN; CORSICO BETINA; FRANCHINI GISELA R.

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN

SPRINGER

Lugar: Berlin; Año: 2020

0920-654X

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 traicking and delivery of such lipophilic metabolites.Pharmacological agents that modify speciic 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 identiied, and 3 of the hits were assayed against puriied E. multilocularis FABP, experimentally conirming the model?s predictions. Noteworthy, this is to our best knowledge the irst report on isolation and puriication of such four FABP, for which initial structural and functional characterization is reported here.