Quantum binding energies of checkpoint CTLA-4 in complex with the immuno-oncological drug ipilimumab.

Inhibition of the checkpoint protein CTLA-4 by the US-FDA's approved monoclonal antibody ipilimumab has delivered breakthrough therapies against a wide range of cancers, being an important issue for clinical research. To date, many structural properties of this drug have been unveiled. However, the binding energy features of the receptor CTLA-4 in complex with its drug inhibitor, based on crystallographic data, need a deeper understanding. Within this context, by employing quantum chemistry we investigate in silico the binding energy features of the checkpoint protein CTLA-4 in complex with its drug inhibitor, highlighting the most relevant residue-residue interactions, looking for new insights into the mechanisms of pathway blockade to further engineer its affinity and selectivity. Our computational results not only give a better understanding of the binding mechanisms, but also point to an efficient alternative towards the development of antibody-based drugs, leading to new treatments for cancer therapy based upon immunotherapy.

Blockade of the checkpoint PD-1 by its ligand PD-L1 and the immuno-oncological drugs pembrolizumab and nivolumab.

We investigate the interaction between the programmed cell death protein 1 (PD-1) and the programmed cell death ligand 1 (PD-L1), as well as the immuno-oncological drugs pembrolizumab (PEM), and nivolumab (NIV), through quantum chemistry methods based on the Density Functional Theory (DFT) and the molecular fractionation with conjugate caps (MFCC) scheme, in order to map their hot-spot regions. Our results showed that the total interaction energy order of the three complexes is in good agreement with the experimental binding affinity order: PD-1/PEM > PD-1/NIV > PD-1/PD-L1. Besides, a detailed investigation revealed the energetically most relevant residue-residue pairs-interaction for each complex. Our computational results give a better understanding of the interaction mechanism between the protein PD-1 and its ligands (natural and inhibitors), unleashing the immune surveillance to destroy the cancer cells by decreasing their immune evasion. They are also an efficient alternative towards the development of new small-molecules and antibody-based drugs, pointing out to new treatments for cancer therapy.

Inhibition of the checkpoint protein PD-1 by the therapeutic antibody pembrolizumab outlined by quantum chemistry.

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.