Quantum biochemistry in cancer immunotherapy: New insights about CTLA-4/ipilimumab and design of ipilimumab-derived peptides with high potential in cancer treatment
| Autor: | Jackson L. Amaral, Hernandes F. Carvalho, Pablo A. de Morais, Valder N. Freire, Samuel José Mendes dos Santos, Pedro F.N. Souza, F. F. Maia |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.drug_class medicine.medical_treatment Immunology Antineoplastic Agents Ipilimumab Molecular Dynamics Simulation Monoclonal antibody 03 medical and health sciences 0302 clinical medicine Electricity Cancer immunotherapy Neoplasms medicine Humans CTLA-4 Antigen Molecular Biology biology Chemistry Cancer Immunotherapy medicine.disease Cancer treatment 030104 developmental biology Biochemistry CTLA-4 Drug Design Proteolysis biology.protein Thermodynamics Antibody Peptides Protein Binding 030215 immunology medicine.drug |
| Zdroj: | Molecular Immunology. 127:203-211 |
| ISSN: | 0161-5890 |
| DOI: | 10.1016/j.molimm.2020.09.013 |
| Popis: | Cancer is a group of diseases involving disordered growth of abnormal cells with the potential to invade and spread to other parts of the body. Today, immunotherapy is the most efficient treatment, with fewer side effects. Notably, the employment of monoclonal antibodies to inhibit checkpoint proteins, such as CTLA-4, has caused much excitement among cancer immunotherapy researchers. Thus, in-depth analysis through quantum biochemistry and molecular dynamics simulations was performed to understand the complex formed by ipilimumab and its target CTLA-4. Our computational results provide a better understanding of the binding mechanisms and new insights about the CTLA-4: ipilimumab interaction, identifying essential amino acid residues to support the complex. Additionally, we report new interactions such as aromatic-aromatic, aromatic-sulfur, and cation-pi interactions to stabilize the CTLA-4:ipilimumab complex. Finally, quantum biochemistry analyses reveal the most important amino acid residues involved in the CTLA-4:ipilimumab interface, which were used to design synthetic peptides to inhibit CTLA-4. The computational results presented here provide a better understanding of the CTLA-4:ipilimumab binding mechanisms, and can support the development of alternative antibody-based drugs with high relevance in cancer immunotherapy. |
| Databáze: | OpenAIRE |
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