Ligand-Protein Interactions of Cymbopogon citratus Compounds and Their Implications for Chagas Disease Treatment.

GÓMEZ CHAVEZ, JOSÉ LEONARDO; CONTI, GERMÁN ANDRES; MIRANDA, MATIAS ORLANDO; ANGELINA, EMILIO LUIS; PERUCHENA, NÉLIDA MARÍA

Rosario

Congreso; XIII CAB2C Congreso Argentino de Bioinformática y Biología Computacional; 2023

Asociación Argentina de Bioinformática y Biología Computacional

The chronic stage of Chagas disease is characterized by severe cardiomyopathyresulting from infection with the parasite Trypanosoma cruzi1. Previous analysis ofthe GSE41089 microarray from NCBI-GEO has revealed key proteins associatedwith this disease. Reverse docking of compounds derived from Cymbopogoncitratus on the key protein targets was applied to prioritize host protein-plantcompound complexes. Molecular dynamics simulations of these complexes havedemonstrated their promising potential as ligands for proteins involved in thisstage of the disease, exhibiting favorable binding energies.This study, which builds upon our previous findings, focused on the investigationof the molecular interactions from the previously prioritized complexes. Theseinteractions may explain the observed effects of the plant on mitigating thispathology by reducing amastigote nests and inflammatory infiltrates in thecardiac tissue of experimental mice2. Ptgs2, Hck, and Csf1r complexes have demonstrated remarkable binding freeenergies (ΔGbind) when compared to specific inhibitors targeting these proteins.Analysis based on the Quantum Theory of Atoms in Molecules (QTAIM) hasrevealed that Ptgs2, for example, exhibits a strong affinity for binding tomolecules that possess both polar and non-polar (unsaturated) moieties, such ascertain terpenes (Fig. 1A). This affinity can be attributed to the characteristic triadpresent in its active site, consisting of arginine, tyrosine, and aspartic acid, whichattract the polar portion of ligands. Moreover, the active site´s abundance ofnon-polar residues facilitates the formation of numerous non-polar interactions,thereby enhancing the stability of the resulting complexes. Similarly, Hck (Fig. 1B)and Csf1r (Fig. 1C) also show a strong tendency to bind to terpenes with structuralunsaturations, leading to the formation of multiple non-polar interactions withinthe complexes.Multiplying the correlation potential (Vc) by the electron density (rho) calculatedfor the complexes allows us to highlight zones of electronic interaction within thesystem. This product provides information about the strength or intensity ofelectronic interactions in different regions of the sample. Consequently, a map orisosurface of the complex is generated, indicating areas with a high probability ofsignificant electronic interactions, with particular emphasis on non-polarinteractions in all complexes (Fig. 1D).Although these non-polar interactions may be weaker compared to polarinteractions, they still contribute to the stabilization and establishment of highaffinity with these complexes.