An inverse docking approach with biological networks to understand the effect of C. Citratus compounds on Chagas disease

Abstract

The chronic stage of Chagas disease is characterized by intense cardiomyopathy caused by infection by the parasite Trypanosoma cruzi. Cymbopogon citratus extracts have been shown to be effective at this stage, relieving this pathology by reducing amastigote nets and inflammatory infiltrates in the cardiac tissue of mice.In this work, bioinformatic tools together with chemoinformatic and virtual screening tools were used to understand the mechanism of action at the molecular level of Cymbopogon citratus extract in chagasic cardiomyopathy.RESULTSThe functional enrichment study of the GSE41089 dataset consisting of gene expression data in the heart of mice infected with T. cruzi versus control, resulted in a set ofoverexpressed genes (logFold-Change>1 and adjusted p-value <0.05) related to GO terms associated with the innate immune response and biological pathways of cytokine release.The Protein-Protein Interaction network built from the overexpressed genes in the most affected biological pathways highlighted those proteins with a high value of interactions in the network. Sequences of the prioritized proteins were aligned against the PDB database with the help of the BLAST engine to retrieve the proteins 3D structures. Native ligands in those structures were cross docked against all the remaining structures to evaluate and improve docking ability to match the known protein-ligand partners. Since selecting targets based on the raw docking scores has been shown to negatively impact the accuracy of reverse docking methods the Z-score metric was used to normalize ligands scores among all protein receptors.The calibrated reverse docking protocol was applied to screen each Cymbopogon citratus component against the prioritized proteins. Molecular Dynamics of the top-ranked complexes confirmed the inverse docking outcomes, including Nerolidol bound to Ptgs2 with a 𝛥G bind similar to specific inhibitors such as diclofenac and ibuprofen.CONCLUSIONSThe combination of network pharmacology strategies together with molecular docking tools results in a promising strategy in the study of the action of plant extracts against Chagas disease and will allow the search for more effective treatments for it.