Synthesis, Pharmacological and Biological Evaluation of 2- Furoyl-based MIF-1 Peptidomimetics, and the Development of a General-Purpose Model for Allosteric Modulators (ALLOPTML)
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| Název: | Synthesis, Pharmacological and Biological Evaluation of 2- Furoyl-based MIF-1 Peptidomimetics, and the Development of a General-Purpose Model for Allosteric Modulators (ALLOPTML) |
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| Autoři: | Dias, Ivo, Rodríguez Borges, José E., Yáñez, Víctor, Arrasate, Sonia, Llorente, Javier, Brea Floriani, José Manuel, Bediaga Bañeres, Harbil, Viña Castelao, María Dolores, Loza García, María Isabel, Olga, Caamaño, García Mera, Xerardo, González-Díaz, Humberto |
| Přispěvatelé: | Universidade de Santiago de Compostela. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica |
| Informace o vydavateli: | American Chemical Society |
| Sbírka: | Minerva - Repositorio institucional da Universidade de Santiago de Compostela (USC) |
| Témata: | Allosteric modulators, Artificial Neural Networks, Big data, ChEMBL, Machine Learning, Melanostatin, Multi-target models, Perturbation Theory |
| Time: | 3209 |
| Popis: | This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in ACS Chemical Neuroscience, copyright © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/acschemneuro.0c00687 ; This work describes the synthesis and pharmacological evaluation of 2-furoyl-based Melanostatin (MIF-1) peptidomimetics as dopamine D2 modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at D2 receptors (D2R). In this series, 2-furoyl-L-leucylglycinamide (6a) produced a statistically significant increase in the maximal [3H]-NPA response at 10 pM (11 ± 1%), comparable to the effect of MIF-1 (22 ± 9%) at the same concentration. This result supports previous evidence that the replacement of proline residue by heteroaromatic scaffolds are tolerated at the allosteric binding site of MIF-1. Biological assays performed for peptidomimetic 6a using cortex neurons from 19-day old Wistar-Kyoto rat embryos suggest 6a displays no neurotoxicity up to 100 μM. Overall, the pharmacological and toxicological profile and the structural simplicity of peptidomimetic 6a makes this peptidomimetic a potential lead compound for further development and optimization, paving the way for the development of novel modulating agents of D2R suitable for the treatment of CNS-related diseases. Additionally, the pharmacological data herein reported was used, along with >20000 outcomes of preclinical assays, to seek a general model to assess the potential of a series of compounds as allosteric modulators for a myriad of receptors targets, organisms, cell lines, and biological activity parameters based on Perturbation Theory (PT) ideas and Machine Learning techniques (ML), abbreviated as ALLOPTML. By doing so, ALLOPTML shows specificity Sp = 89.2/89.4% and sensitivity Sn = 71.3/72.2% in training/validation series, respectively. To the best of our knowledge, ... |
| Druh dokumentu: | article in journal/newspaper |
| Jazyk: | English |
| Relation: | https://doi.org/10.1021/acschemneuro.0c00687; FCT -- UIDB/50006/2020; FEDER -- CTQ2016-74881-P; http://hdl.handle.net/10347/32607 |
| DOI: | 10.1021/ACSCHEMNEURO.0C00687 |
| Dostupnost: | http://hdl.handle.net/10347/32607 https://doi.org/10.1021/ACSCHEMNEURO.0C00687 |
| Rights: | Copyright © 2020 American Chemical Society ; open access |
| Přístupové číslo: | edsbas.27A7AA4E |
| Databáze: | BASE |
Nájsť tento článok vo Web of Science | Abstrakt: | This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in ACS Chemical Neuroscience, copyright © American Chemical Society after peer review. To access the final edited and published work see https://doi.org/10.1021/acschemneuro.0c00687 ; This work describes the synthesis and pharmacological evaluation of 2-furoyl-based Melanostatin (MIF-1) peptidomimetics as dopamine D2 modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at D2 receptors (D2R). In this series, 2-furoyl-L-leucylglycinamide (6a) produced a statistically significant increase in the maximal [3H]-NPA response at 10 pM (11 ± 1%), comparable to the effect of MIF-1 (22 ± 9%) at the same concentration. This result supports previous evidence that the replacement of proline residue by heteroaromatic scaffolds are tolerated at the allosteric binding site of MIF-1. Biological assays performed for peptidomimetic 6a using cortex neurons from 19-day old Wistar-Kyoto rat embryos suggest 6a displays no neurotoxicity up to 100 μM. Overall, the pharmacological and toxicological profile and the structural simplicity of peptidomimetic 6a makes this peptidomimetic a potential lead compound for further development and optimization, paving the way for the development of novel modulating agents of D2R suitable for the treatment of CNS-related diseases. Additionally, the pharmacological data herein reported was used, along with >20000 outcomes of preclinical assays, to seek a general model to assess the potential of a series of compounds as allosteric modulators for a myriad of receptors targets, organisms, cell lines, and biological activity parameters based on Perturbation Theory (PT) ideas and Machine Learning techniques (ML), abbreviated as ALLOPTML. By doing so, ALLOPTML shows specificity Sp = 89.2/89.4% and sensitivity Sn = 71.3/72.2% in training/validation series, respectively. To the best of our knowledge, ... |
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| DOI: | 10.1021/ACSCHEMNEURO.0C00687 |