Interação PD-1::PD-L1: dinâmica molecular bioquímica quântica do anticorpo atezolizumabe aliado ao desenho racional de peptídeos com potencial aplicação no tratamento de câncer

Abstract

Cancer is the second leading cause of death worldwide, accounting for approximately 9.6 million deaths or one in every six deaths in 2018. The disease is characterized by the uncontrolled growth of abnormal cells in the body. These cells, known as cancer cells, have the ability to invade healthy tissues and spread to other parts of the body through a process called metastasis. Among the currently available cancer treatments, immunotherapy has emerged as a prominent and effective approach for treating various types of cancer, including melanoma, lung cancer, kidney cancer, bladder cancer, and others. Immunotherapy has shown long-lasting benefits and significant responses, even in advanced cases, and its specificity is based on the use of antibodies with specific targets. Antibodies targeting the PD-1::PD-L1 pathway, such as Pembrolizumab, Nivolumab, and Atezolizumabe, are already available on the market. In this study, classical molecular dynamics simulations and quantum simulations using Density Functional Theory (DFT) were employed to elucidate the interactions between the chains of the Atezolizumabe antibody, which acts as an inhibitor, and PD-L1 upon contact with PD-1, which is present on T cells. PD-1 stimulates the protein that is overexpressed in cancer cells and makes them less susceptible to apoptosis, as measured by the cells. The results obtained indicated that the main regions responsible for binding affinities at the interfaces of the PD-L1::Atezolizumabe complex system were the Heavy Chain (HC) and the Light Chain (LC). The residues with the most energetic contributions were as follows: TYR54, GLY55, GLY56, SER57, THR58, TYR59, and TYR60 in the Heavy Chain (HC), and TYR91, LEU92, TYR93, HIS94, and PRO95 in the Light Chain (LC). Therefore, the DFT description was able to provide detailed insights into the binding mechanisms through the inhibitory effect of the antibody, enabling the design of peptides that could potentially be used to treat patients with different types of cancer.