Detecção de compostos fitoquímicos com potencial atividade seletiva-inibitória dos sitios de ligação na isoforma da AKT-1 humana

Abstract

The Akt protein is involved in various metabolic cellular processes, especially in the regulation of cell survival. In its active form, it promotes the phosphorylation of various proteins involved in cell multiplication factors and inhibits others related to apoptosis. When hyperactivated, it overloads the cell proliferation pathway and can produce tumors. Actions such as these can increase resistance to various compounds that act to inhibit cell growth, such as chemotherapy drugs, making this protein an important therapeutic target in the development of cancer treatments. This work focuses on the specific analysis of the Akt protein, especially isoform 1 (Akt1), since of the three known isoforms it is the most explored and is directly related to neoplasms. In order to discover potential molecules of plant origin that bind to the active site and promote competitive inhibition, we evaluated existing mechanisms by searching for crystallographic data related to Akt1 and produced models with good resolution for testing with various computational tools. We used software to identify the conformational states of the protein, compared all the structures found with the positions of the ligands in the catalytic sites and in order to discover the best representative models for this protein, we produced simple and cross molecular docking (Self-Docking and Cross-Docking). We found 3 main interaction sites in Akt1: the plecstrin homology site (PH site), the main kinase activity site (Site 1) and the protein interaction site (Site 2). The models that showed the best energy and ligand distance (RMSD) results with the crystallographic data went on to the virtual screening stage. At this stage, we used approximately 1800 compounds of plant origin (COVs) deposited in the Brazilian Natural Products Database (NuBBEDB). In short, the test results were promising, showing strong and persistent bonds between the molecules studied. We found 8 main compounds, including flavonoids and terpenes, which had the best interaction energies between -11.7kCal and -10.9kCal. These compounds share characteristics with other molecules used in the treatment of various pathologies, which have low toxic potential. Therefore, the use of the molecules found in this work for more specific tests may favor the development of new drugs related to the competitive inhibition of the Akt1 active site.