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Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations

[Image: see text] The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmac...

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Autores principales: Gervasoni, Silvia, Öztürk, Işılay, Guccione, Camilla, Bosin, Andrea, Ruggerone, Paolo, Malloci, Giuliano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2023
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10428218/
https://www.ncbi.nlm.nih.gov/pubmed/37466559
http://dx.doi.org/10.1021/acs.jcim.3c00712
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author Gervasoni, Silvia
Öztürk, Işılay
Guccione, Camilla
Bosin, Andrea
Ruggerone, Paolo
Malloci, Giuliano
author_facet Gervasoni, Silvia
Öztürk, Işılay
Guccione, Camilla
Bosin, Andrea
Ruggerone, Paolo
Malloci, Giuliano
author_sort Gervasoni, Silvia
collection PubMed
description [Image: see text] The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticals are composed of a somatostatin analogue biovector conjugated to a chelator moiety bearing the radionuclide. To date, despite valuable efforts, a detailed molecular-level description of the interaction of radiopharmaceuticals in complex with SSTR2 has not yet been accomplished. Therefore, in this work, we carefully analyzed the key dynamical features and detailed molecular interactions of SSTR2 in complex with six radiopharmaceutical compounds selected among the few already in use ((64)Cu/(68)Ga-DOTATATE, (68)Ga-DOTATOC, (64)Cu-SARTATE) and some in clinical development ((68)Ga-DOTANOC, (64)Cu-TETATATE). Through molecular dynamics simulations and exploiting recently available structures of SSTR2, we explored the influence of the different portions of the compounds (peptide, radionuclide, and chelator) in the interaction with the receptor. We identified the most stable binding modes and found distinct interaction patterns characterizing the six compounds. We thus unveiled detailed molecular interactions crucial for the recognition of this class of radiopharmaceuticals. The microscopically well-founded analysis presented in this study provides guidelines for the design of new potent ligands targeting SSTR2.
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spelling pubmed-104282182023-08-17 Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations Gervasoni, Silvia Öztürk, Işılay Guccione, Camilla Bosin, Andrea Ruggerone, Paolo Malloci, Giuliano J Chem Inf Model [Image: see text] The development of drugs targeting somatostatin receptor 2 (SSTR2), generally overexpressed in neuroendocrine tumors, is focus of intense research. A few molecules in conjugation with radionuclides are in clinical use for both diagnostic and therapeutic purposes. These radiopharmaceuticals are composed of a somatostatin analogue biovector conjugated to a chelator moiety bearing the radionuclide. To date, despite valuable efforts, a detailed molecular-level description of the interaction of radiopharmaceuticals in complex with SSTR2 has not yet been accomplished. Therefore, in this work, we carefully analyzed the key dynamical features and detailed molecular interactions of SSTR2 in complex with six radiopharmaceutical compounds selected among the few already in use ((64)Cu/(68)Ga-DOTATATE, (68)Ga-DOTATOC, (64)Cu-SARTATE) and some in clinical development ((68)Ga-DOTANOC, (64)Cu-TETATATE). Through molecular dynamics simulations and exploiting recently available structures of SSTR2, we explored the influence of the different portions of the compounds (peptide, radionuclide, and chelator) in the interaction with the receptor. We identified the most stable binding modes and found distinct interaction patterns characterizing the six compounds. We thus unveiled detailed molecular interactions crucial for the recognition of this class of radiopharmaceuticals. The microscopically well-founded analysis presented in this study provides guidelines for the design of new potent ligands targeting SSTR2. American Chemical Society 2023-07-19 /pmc/articles/PMC10428218/ /pubmed/37466559 http://dx.doi.org/10.1021/acs.jcim.3c00712 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Gervasoni, Silvia
Öztürk, Işılay
Guccione, Camilla
Bosin, Andrea
Ruggerone, Paolo
Malloci, Giuliano
Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations
title Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations
title_full Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations
title_fullStr Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations
title_full_unstemmed Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations
title_short Interaction of Radiopharmaceuticals with Somatostatin Receptor 2 Revealed by Molecular Dynamics Simulations
title_sort interaction of radiopharmaceuticals with somatostatin receptor 2 revealed by molecular dynamics simulations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10428218/
https://www.ncbi.nlm.nih.gov/pubmed/37466559
http://dx.doi.org/10.1021/acs.jcim.3c00712
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