Abstract
Much of the recent excitement in the cancer immunotherapy approach has been generated by the recognition that immune checkpoint proteins, like the receptor PD-1, can be blocked by antibody-based drugs with profound effects. Promising clinical data have already been released pointing to the efficiency of the drug pembrolizumab to block the PD-1 pathway, triggering the T-lymphocytes to destroy the cancer cells. Thus, a deep understanding of this drug/receptor complex is essential for the improvement of new drugs targeting the protein PD-1. In this context, by employing quantum chemistry methods based on the Density Functional Theory (DFT), we investigate in silico the binding energy features of the receptor PD-1 in complex with its drug inhibitor. Our computational results give a better understanding of the binding mechanisms, being also an efficient alternative towards the development of antibody-based drugs, pointing to new treatments for cancer therapy.
Highlights
The World Health Organization (WHO) labels cancer as one of the most pressing health challenges in the world
These mutations provide a selective vantage to populations of cancer cells, they increase their divergences from the normal one, which can allow the recognition by the immune system cells, such as the T lymphocytes (T cells) and B cells[7]
The molecular identification of cancer antigens helped the creation of new approaches for effective therapies, giving rise to a new era of treatment in which our own immune system evade the block created by malignant cells and fights against them
Summary
The World Health Organization (WHO) labels cancer as one of the most pressing health challenges in the world. Cancer is a leading cause of death, accounting for over 8.8 million casualties and 14.1 million cases diagnosed worldwide in 2015, numbers that are expected to increase in the coming years[1] It is characterized by an uncontrolled growth of cells in the body, with the potential to invade or spread to its other parts with the formation of metastases. Though highly expensive, the treatment suffers several fails due to a defense mechanisms developed by some malignant cells, mainly those related to the activation of drug resistance processes[6] These mutations provide a selective vantage to populations of cancer cells, they increase their divergences from the normal one, which can allow the recognition by the immune system cells, such as the T lymphocytes (T cells) and B cells[7]. A comparison among them allow us to describe the PD-1 extracellular domain in a canonical IgV-type topology containing a β-sandwich arrangement formed by front and back β-strand faces of interacting domains, GFCC’ and ABED β-sheets, respectively (for a review see ref.[20])
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