Busca in silico de substâncias bioativas presentes na espécie Euphorbia tirucalli como potenciais agentes anticancerígenos contra o câncer colorretal.

Abstract

Colorectal cancer (CRC) is the third most common type of cancer, affecting the large intestine and rectum, caused by the accumulation of genetic and epigenetic alterations. The dysregulation of cellular signaling pathways, such as PI3K, mTOR, ERK/MAPK, TNF-α, and TGF-β, contributes to CRC development. Euphorbia tirucalli, a plant known as "aveloz", contains flavonoids like kaempferol, isoquercetin, and quercetin, with anti-tumor activities. A table with 63 important proteins in the CRC signaling pathway was created, selecting five target proteins. Flexible alignment models of flavonoids resulted in the selection of model 4, followed by verification of pharmacophoric points and the construction of a unique structure, named Flavo1. The Flavo1 molecule was optimized to improve its therapeutic efficacy, leading to the development of Flavo2. The volume of Flavo2 is 378.867 units and its density is 1.04. It has 8.0 acceptors and 6.0 hydrogen bond donors, within acceptable limits. Flavo2 has an average QED of 0.67 for attractive compounds, 0.49 for non-attractive, and 0.34 for highly complex non-attractive compounds. Its predicted Caco-2 permeability is expressed as -5.301 log cm/s, approximately 0.151 below the considered good value (> -5.15 log cm/s). Flavo2 obtained Caco-2 permeability below the considered good limit and showed stability and low likelihood of hepatic clearance, being an aromatase inhibitor that may affect hormonal balance. For complex validation, re-docking was necessary, except for TGF-β, which was not coupled with a ligand. The interaction between Flavo2 and mTOR resulted in a binding energy of -8.74, involving 12 ligands in the ATP site of mTOR. Flavo2 showed a close interaction to the drug PI-103, with a binding energy of -8.78. With PI3K, Flavo2 presented a binding energy of -7.89, with significant interaction with the crucial residue. The interaction with ERK2 resulted in a binding energy of -7.64, while with ulixertinibe it was -7.65. The docking with TGFβR1 showed a strong interaction, with a binding energy of -9.80, while with Galunisertib, it was slightly higher by about 0.15. With TNF-α, Flavo2 had a binding energy of -7.69, while with SPD304, it was -7.60, lower than Flavo2. When comparing the compound Flavo2 with a synthetic drug, it was observed that the binding energy of Flavo2 was higher in proteins such as PI3K and TNF-α. However, no significant differences were observed concerning the other studied proteins. It is important to note that additional tests are needed to validate these results and improve the pharmacokinetic properties of Flavo2. These steps are crucial for the development of new, effective, and safe drugs for the treatment of colorectal cancer.