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Computationally-obtained structural insights into the molecular interactions between Pidilizumab and binding partners DLL1 and PD-1.
Albuquerque, Aline de Oliveira; da Silva Junior, Haroldo Cid; Sartori, Geraldo Rodrigues; Martins da Silva, João Hermínio.
Afiliação
  • Albuquerque AO; Programa de Pós-graduação em Biotecnologia de Recursos Naturais, Universidade Federal do Ceará, Fortaleza, Brazil.
  • da Silva Junior HC; Laboratório de Tecnologia Recombinante, Bio-Manguinhos/Fiocruz, Rio de Janeiro, Brazil.
  • Sartori GR; Grupo para Modelagem, Simulação e Evolução, in sílico, de Biomoléculas, Fiocruz-Ceará, Eusébio, Brazil.
  • Martins da Silva JH; Grupo para Modelagem, Simulação e Evolução, in sílico, de Biomoléculas, Fiocruz-Ceará, Eusébio, Brazil.
J Biomol Struct Dyn ; 40(14): 6450-6462, 2022 09.
Article em En | MEDLINE | ID: mdl-33559526
Pidilizumab is a monoclonal antibody tested against several types of malignancies, such as lymphoma and metastatic melanoma, showing promising results. In 2016, the FDA put Pidilizumab's clinical studies on partial hold due to emerging evidence pointing to the antibody target uncertainty. Although initial studies indicated an interaction with the PD-1 checkpoint receptor, recent updates assert that Pidilizumab binds primarily to Notch ligand DLL1. However, a detailed description of which interactions coordinate antibody-antigen complex formation is lacking. Therefore, this study uses computational tools to identify molecular interactions between Pidilizumab and its reported targets PD-1 and DLL1. A docking methodology was validated and applied to determine the binding modes between modeled Pidilizumab scFvs and the two antigens. We used Molecular Dynamics (MD) simulations to verify the complexes' stability and submitted the resulting trajectory files to MM/PBSA and Principal Component Analysis. A set of different prediction tools determined scFv interface hot-spots. Whereas docking and MD simulations revealed that the antibody fragments do not interact straightforwardly with PD-1, ten scFv hot-spots, including Met93 and Leu112, mediated the interaction with the DLL1 C2 domain. The interaction triggered a conformational selection-like effect on DLL1, allowing new hydrogen bonds on the ß3-ß4 interface loop. The unprecedented structural data on Pidilizumab's interactions provided novel evidence that its legitimate target is the DLL1 protein and offered structural insight on how these molecules interact, shedding light on the pathways that could be affected by the use of this essential immunobiological. Communicated by Ramaswamy H. Sarma.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptor de Morte Celular Programada 1 / Anticorpos Monoclonais Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Receptor de Morte Celular Programada 1 / Anticorpos Monoclonais Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2022 Tipo de documento: Article