Date Published: May 15, 2015
Publisher: Public Library of Science
Author(s): Lilian Hernández Alvarez, Dany Naranjo Feliciano, Jorge Enrique Hernández González, Rosemberg de Oliveira Soares, Diego Enry Barreto Gomes, Pedro Geraldo Pascutti, John Pius Dalton. http://doi.org/10.1371/journal.pntd.0003759
Abstract: BackgroundFasciola hepatica is the causative agent of fascioliasis, a disease affecting grazing animals, causing economic losses in global agriculture and currently being an important human zoonosis. Overuse of chemotherapeutics against fascioliasis has increased the populations of drug resistant parasites. F. hepatica cathepsin L3 is a protease that plays important roles during the life cycle of fluke. Due to its particular collagenolytic activity it is considered an attractive target against the infective phase of F. hepatica.Methodology/Principal FindingsStarting with a three dimensional model of FhCL3 we performed a structure-based design of novel inhibitors through a computational study that combined virtual screening, molecular dynamics simulations, and binding free energy (ΔGbind) calculations. Virtual screening was carried out by docking inhibitors obtained from the MYBRIDGE-HitFinder database inside FhCL3 and human cathepsin L substrate-binding sites. On the basis of dock-scores, five compounds were predicted as selective inhibitors of FhCL3. Molecular dynamic simulations were performed and, subsequently, an end-point method was employed to predict ΔGbind values. Two compounds with the best ΔGbind values (-10.68 kcal/mol and -7.16 kcal/mol), comparable to that of the positive control (-10.55 kcal/mol), were identified. A similar approach was followed to structurally and energetically characterize the interface of FhCL3 in complex with a peptidic substrate. Finally, through pair-wise and per-residue free energy decomposition we identified residues that are critical for the substrate/ligand binding and for the enzyme specificity.Conclusions/SignificanceThe present study is the first computer-aided drug design approach against F. hepatica cathepsins. Here we predict the principal determinants of binding of FhCL3 in complex with a natural substrate by detailed energetic characterization of protease interaction surface. We also propose novel compounds as FhCL3 inhibitors. Overall, these results will foster the future rational design of new inhibitors against FhCL3, as well as other F. hepatica cathepsins.
Partial Text: Fascioliasis or hepatic distomatosis, caused by the food-borne trematodes Fasciola hepatica and Fasciola gigantica, is considered one of the most important parasitic diseases, which constitutes a serious public health problem and has a significant veterinary relevance. Economically important animals affected by this disease include cattle, sheep and goats [1, 2]. Fascioliasis symptoms are host-specific, but generally comprise reduced milk and wool yields, weight gains, and fertility . Recently, the global burden of fascioliasis was calculated and it has been estimated that 2.6 million people are infected with Fasciola spp. .