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Issue 10, 2019
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Structural insights and binding analysis for determining the molecular bases for programmed cell death protein ligand-1 inhibition

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Abstract

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) interaction plays an important role in cancer immunotherapy. Several PD-1/PD-L1 inhibitors have been approved with remarkable impact on overall patient survival rates. Inhibitors in clinical practice are presently limited to monoclonal antibodies. However, their severe shortcomings expose the need for a new generation of PD-L1 inhibitors. Understanding the tumor microenvironment, identifying specific biomarkers and X-ray crystalline structures of PD-1/PD-L1 complexes, including molecular and genomic signature studies are essential to determine the success for the development of PD-1/PD-L1 inhibitors into safer and efficient cancer immunotherapeutics. Currently, the development of immune-modulatory small molecules is being explored due to their benefits over recombinant protein approaches. Nevertheless, their development is hampered in part due to lack of structural information. The current study builds on PD-L1 small-molecule inhibitor structural information and provides insights into the design of new inhibitors. To this end, a comprehensive analysis of crystallographic structures and benchmarking studies were performed, showing the specific structure model and software best suited to study PD-L1. The use of in silico methodologies can give a deeper insight to guide the design of novel PD-L1 small-molecule inhibitors.

Graphical abstract: Structural insights and binding analysis for determining the molecular bases for programmed cell death protein ligand-1 inhibition

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Publication details

The article was received on 11 Jun 2019, accepted on 24 Jul 2019 and first published on 29 Jul 2019


Article type: Research Article
DOI: 10.1039/C9MD00326F
Med. Chem. Commun., 2019,10, 1810-1818

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    Structural insights and binding analysis for determining the molecular bases for programmed cell death protein ligand-1 inhibition

    R. C. Acúrcio, C. Leonardo-Sousa, A. T. García-Sosa, J. A. Salvador, H. F. Florindo and R. C. Guedes, Med. Chem. Commun., 2019, 10, 1810
    DOI: 10.1039/C9MD00326F

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