Simulação quântica computacional de fármacos imuno-oncológicos

Abstract

Much of the recent excitement in the cancer immunotherapy approach has been generated by the recognition that immune checkpoint proteins, like the receptors PD-1 (Programmed cell Death-Ligand 1) and CTLA-4 (Cytotoxic T-Lymphocyte-Associated Protein 4), can be blocked by antibody-based drugs, with deeper effects. Promising clinical data have already been released, pointing out to the efficiency of the monoclonal antibody immune-oncological drugs pembrolizumab (PEM), nivolumab (NIV), and ipilimumab (IPI) to block these immune checkpoint proteins pathway, triggering the T-lymphocytes against a wide range of cancers, as well as being an important issue for clinical research. Their use was already approved by the US-FDA (United States-Food and Drug Administration) office since the last decade. To date, although many structural properties of these drugs have been unveiled, binding energy features of both checkpoint proteins, PD-1 and CTLA-4, based on crystallographic X-Ray data, need a deeper understanding. In this context, by employing quantum chemistry methods based on the Density Functional Theory (DFT) and the molecular fractionation with conjugate caps (MFCC) scheme, we investigate in silico the binding energy features of the receptors PD-1 and CTLA-4 in complex with their drugs inhibitor (PEM, NIV, and IPI), highlighting the most relevant residue-residue interactions, looking for new insights into the mechanisms of the pathway blockade to further engineer their affinity and selectivity. Our computational results are not only in good agreement with the experimental binding affinity order, but also give a better understanding of the binding mechanisms, pointing out to an efficient alternative towards the development of antibody-based drugs. Besides, they lead to new treatments for cancer therapy based upon immunotherapy, 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, unveiling new treatments for cancer therapy. On the other hand, although many structural properties of these immune-oncological drugs have been unveiled, only few studies were focused on their vibrational features. To fill this gap, quantum chemistry calculations were also employed here to depict the binding energetic modes of the PEM and NIV antibody drugs, in order to obtain their vibrational properties through their optical absorption spectra and Raman scattering spectroscopy. Detailed interpretation of their harmonic vibrational frequencies is also presented. Finally, the binding of three different anticancer drugs, Cu(BpT)Br, NAMI-A, and DOX (doxorubicin), widely used in the breast cancer treatment, to the Human Serum Albumin (HSA), were also investigated here by means of a dispersion corrected exchange-correlation functional within a fragmentation strategy. As a consequence, it is possible to identify the magnitude of the most relevant quantum binding interactions of these supramolecular complexes, and thus guide their molecular modification process. The data obtained in this work highlight the power of quantum calculations as an important tool for the drug design process, and pave the way for the use of HSA-ligand interactions during the rational design of new anticancer compounds. More important, our results show that HSA/[Cu(BpT)Br]–(NAMI-A)-(DOX) multi-drug complex increases the targeting ability compared with the isolated use of the three anticancer-drugs, in agreement with in vivo predictions. All in all, the quantum chemistry computational methods used in this PhD thesis emerged as a simple and efficient alternative to unveil the drug’s amino-acids residues that play the most important role on the binding affinity of the receptor-ligand complex. Indeed, taking into account the cost/benefit of the operation, in silico approach is becoming an important initial step not only in clinical oncology, but also in defining the research frontier in the biological, physical and chemical science.