Inibição do câncer de mama utilizando imunoterapia através de uma modelagem computacional quântica

Abstract

During immunosurveillance, the immune system is capable to recognize and destroy tumor cells by the activation of the so-called immunological checking points, essential to avoid autoimmune events, creating barriers to the T-cell activation and tumor rejection. One of the foremost inhibitory pathways is done by the PD-1 protein (Programmed cell death protein-1), which is activated by several types of cancerous tumors, and is now considered a new and important therapeutic approach for the treatment of cancer in general, including breast cancer. Several immune checkpoint inhibitor antibodies are already approved by the US-FDA (United States - Food and Drug Administration) to bind the protein PD-1, disrupting its interaction with the PD-L1 and PD-L2 ligands, thereby attenuating inhibitory signals and augmenting the host anti-tumor response. Among them, the drug pembrolizumab, an immune checkpoint inhibitor antibody, is being widely used to efficiently blocks a protective mechanism on cancer cells, triggering the T-cells to destroy them. The aim of this work is to describe the interaction energies between the protein PD-1 and its drug inhibitor pembrolizumab by using a quantum biochemistry calculation, taking advantage of the X-ray crystal structure of the protein PD-1 in complex with its inhibitor. The interaction energy between each PD-1 molecule and the drug was calculated in silico through quantum chemistry approaches considering any significant attractive and repulsive drug’s amino acid residues. Although it was observed few repulsive interactions, the attractive ones were predominant, pointing out to a strong inhibition of the programmed cell death receptor. Besides, several biochemical aspects were analyzed, especially those related to the immune checking points. Our results show that the computational method used in this work is a low cost efficient first step to unveil the drug’s amino-acids residues that play the most important role on the binding affinity of the pembrolizumab/PD-1 complex. Besides, it can be considered a great qualitative step for immunotherapy to become one of the standard tools leading to the development of new and effective cancer drugs.