LIGAND-PROTEIN INTERACTIONS OF CYMBOPOGON CITRATUS COMPOUNDS AND THEIR IMPLICATIONS FOR CHAGAS DISEASE TREATMENT.

GOMEZ CHAVEZ, JOSE LEONARDO; CONTI, GERMAN; MIRANDA, MATIAS ; ANGELINA, EMILIO; PERUCHENA, N. M.

ROSARIO SANTA FE

Congreso; XIII CAB2C - 13th Argentinian Conference in Bioinformatics and Computational Biology XIII SoIBio - 13th International Conference of the Iberoamerican Society of ología Computacional Lugar: Rosario; 2023.; 2023

Asociación Argentina de Bioinformática y Biología Computacional

The chronic stage of Chagas disease is characterized by severe cardiomyopathy resulting from infection with the parasite Trypanosoma cruzi [1]. Previous analysis of the GSE41089 microarray from NCBI-GEO has revealed key proteins associated with this disease. Reverse docking of compounds derived from Cymbopogon citratus on the key protein targets was applied to prioritize host protein-plant compound complexes. Molecular dynamics simulations of these complexes have demonstrated their promising potential as ligands for proteins involved in this stage of the disease, exhibiting favorable binding energies. This study, which builds upon our previous findings, focused on the investigation of the molecular interactions from the previously prioritized complexes. These interactions may explain the observed effects of the plant on mitigating this pathology by reducing amastigote nests and inflammatory infiltrates in the cardiac tissue of experimental mice2. Ptgs2, Hck, and Csf1r complexes have demonstrated remarkable binding free energies (ΔGbind) when compared to specific inhibitors targeting these proteins. Analysis based on the Quantum Theory of Atoms in Molecules (QTAIM) has revealed that Ptgs2, for example, exhibits a strong affinity for binding to molecules that possess both polar and non-polar (unsaturated) moieties, such as certain terpenes (Fig. 1A). This affinity can be attributed to the characteristic triad present in its active site, consisting of arginine, tyrosine, and aspartic acid, which attract the polar portion of ligands. Moreover, the active site´s abundance of non-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 structural unsaturations, leading to the formation of multiple non-polar interactions within the complexes. Multiplying the correlation potential (Vc) by the electron density (rho) calculated for the complexes allows us to highlight zones of electronic interaction within the system. This product provides information about the strength or intensity of electronic interactions in different regions of the sample. Consequently, a map or iso surface of the complex is generated, indicating areas with a high probability of significant electronic interactions, with particular emphasis on non-polar interactions in all complexes (Fig. 1D).Although these non-polar interactions may be weaker compared to polar interactions, they still contribute to the stabilization and establishment of high affinity with these complexes.