A quantum biochemistry approach to investigate checkpoint inhibitor drugs for cancer

Abstract

Targeted immunotherapy has reignited enthusiasm for the development of checkpoint inhibitor drugs for cancer, noticeably improving the overall survival of cancer patients. In this sense, the inhibition of the programmed cell death receptor-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway by the US FDA-approved monoclonal antibodies Pembrolizumab and Nivolumab, the leading drugs of this therapeutic revolution, was recognized as an important issue for clinical research. Although the drug's immune-related binding interactions to PD-1 are slightly different, they competitively hinder the natural ligand PD-L1. Besides, their binding energy features undoubtedly need to be better understood to assure their safe use as new medicines in clinical practice. In this context, by employing quantum chemistry methods based on density functional theory (DFT), we investigate in silico the coupling profiles of the receptor PD-1 in complex with its natural ligand PDL-1 and these two drug inhibitors, looking for a better understanding of their binding interactions, essential to validate their importance in the PD-1/PDL-1 pathway blockade for the treatment of malignant melanomas.