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A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core

Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochem...

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Autores principales: García‐Marín, Javier, Griera, Mercedes, Alajarín, Ramón, Rodríguez‐Puyol, Manuel, Rodríguez‐Puyol, Diego, Vaquero, Juan J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518816/
https://www.ncbi.nlm.nih.gov/pubmed/34137509
http://dx.doi.org/10.1002/cmdc.202100338
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author García‐Marín, Javier
Griera, Mercedes
Alajarín, Ramón
Rodríguez‐Puyol, Manuel
Rodríguez‐Puyol, Diego
Vaquero, Juan J.
author_facet García‐Marín, Javier
Griera, Mercedes
Alajarín, Ramón
Rodríguez‐Puyol, Manuel
Rodríguez‐Puyol, Diego
Vaquero, Juan J.
author_sort García‐Marín, Javier
collection PubMed
description Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochemical mechanism and functions are still being studied. In the present study, based on our experience generating PTP1B inhibitors, we have developed and implemented a scaffold‐hopping approach to vary the pyrrole ring of the pyrrolo[1,2‐a]quinoxaline core, supported by extensive computational techniques aimed to explain the molecular interaction with PTP1B. Using a combination of docking, molecular dynamics and end‐point free‐energy calculations, we have rationally designed a hypothesis for new PTP1B inhibitors, supporting their recognition mechanism at a molecular level. After the design phase, we were able to easily synthesize proposed candidates and their evaluation against PTP1B was found to be in good concordance with our predictions. Moreover, the best candidates exhibited glucose uptake increments in cellulo model, thus confirming their utility for PTP1B inhibition and validating this approach for inhibitors design and molecules thus obtained.
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spelling pubmed-85188162021-10-21 A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core García‐Marín, Javier Griera, Mercedes Alajarín, Ramón Rodríguez‐Puyol, Manuel Rodríguez‐Puyol, Diego Vaquero, Juan J. ChemMedChem Full Papers Protein tyrosine phosphatase 1B (PTP1B) is a very promising target for the treatment of metabolic disorders such as type II diabetes mellitus. Although it was validated as a promising target for this disease more than 30 years ago, as yet there is no drug in advanced clinical trials, and its biochemical mechanism and functions are still being studied. In the present study, based on our experience generating PTP1B inhibitors, we have developed and implemented a scaffold‐hopping approach to vary the pyrrole ring of the pyrrolo[1,2‐a]quinoxaline core, supported by extensive computational techniques aimed to explain the molecular interaction with PTP1B. Using a combination of docking, molecular dynamics and end‐point free‐energy calculations, we have rationally designed a hypothesis for new PTP1B inhibitors, supporting their recognition mechanism at a molecular level. After the design phase, we were able to easily synthesize proposed candidates and their evaluation against PTP1B was found to be in good concordance with our predictions. Moreover, the best candidates exhibited glucose uptake increments in cellulo model, thus confirming their utility for PTP1B inhibition and validating this approach for inhibitors design and molecules thus obtained. John Wiley and Sons Inc. 2021-07-19 2021-09-16 /pmc/articles/PMC8518816/ /pubmed/34137509 http://dx.doi.org/10.1002/cmdc.202100338 Text en © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Full Papers
García‐Marín, Javier
Griera, Mercedes
Alajarín, Ramón
Rodríguez‐Puyol, Manuel
Rodríguez‐Puyol, Diego
Vaquero, Juan J.
A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core
title A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core
title_full A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core
title_fullStr A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core
title_full_unstemmed A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core
title_short A Computer‐Driven Scaffold‐Hopping Approach Generating New PTP1B Inhibitors from the Pyrrolo[1,2‐a]quinoxaline Core
title_sort computer‐driven scaffold‐hopping approach generating new ptp1b inhibitors from the pyrrolo[1,2‐a]quinoxaline core
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8518816/
https://www.ncbi.nlm.nih.gov/pubmed/34137509
http://dx.doi.org/10.1002/cmdc.202100338
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