Inibidores de segunda geração e a via PI3K/AKT/MTOR: caracterização por modelagem molecular

Abstract

The PI3K/Akt/mTOR signaling pathway plays a crucial role in regulating various cellular processes, including the cell cycle, cell survival, glucose and lipid metabolism, and apoptosis. This complex mechanism involves more than 150 proteins and responds to extracellular signals, such as growth factors and nutrients, being essential for maintaining cellular homeostasis. Dysfunction of this pathway is closely associated with the development of several diseases, including cancer, cardiovascular diseases, and neurodegenerative disorders. In particular, within the context of cancer, hyperactivation of the PI3K/Akt/mTOR pathway has been strongly linked to uncontrolled cell proliferation, resistance to apoptosis, and cell survival processes that together contribute to tumor growth and progression. These factors make the PI3K/Akt/mTOR pathway a highly important therapeutic target for cancer treatment. Understanding the mechanisms of activation and inhibition of this pathway provides the necessary knowledge for developing specific inhibitors of PI3Kα and mTOR proteins. Selective or simultaneous inhibition of these proteins can disrupt dysregulated signaling and, consequently, reduce tumor growth and enhance treatment efficacy. The identification of effective and selective inhibitors that can interfere with the activity of this pathway is highlighted in the literature as an emerging research target in medicinal chemistry. To achieve this goal, the application of computational techniques, such as molecular docking, has proven to be a fundamental methodology for optimizing time and accuracy in drug development. In this work, molecular descriptors based on the interaction energies between the ligands and the active site residues of the enzymes were correlated with biological activity (pIC₅₀) using multiple linear regression (MLR). The models showed good correlation and enabled the identification of key residues associated with inhibitor potency. The PA1–PA5 compounds demonstrated that bulky substituents at R3 favor selectivity for mTOR, while smaller groups at R1 favor PI3Kα. The PB1–PB5 compounds confirmed that small modifications at R3 modulate enzyme selectivity, with PB1 standing out for mTOR selectivity and PB3 showing potential for dual inhibition.