RT Journal Article
T1 Synthesis, Pharmacological and Biological Evaluation of 2- Furoyl-based MIF-1 Peptidomimetics, and the Development of a General-Purpose Model for Allosteric Modulators (ALLOPTML)
A1 Dias, Ivo
A1 Rodríguez Borges, José E.
A1 Yáñez, Víctor
A1 Arrasate, Sonia
A1 Llorente, Javier
A1 Brea Floriani, José Manuel
A1 Bediaga Bañeres, Harbil
A1 Viña Castelao, María Dolores
A1 Loza García, María Isabel
A1 Olga, Caamaño
A1 García Mera, Xerardo
A1 González-Díaz, Humberto
K1 Allosteric modulators
K1 Artificial Neural Networks
K1 Big data
K1 ChEMBL
K1 Machine Learning
K1 Melanostatin
K1 Multi-target models
K1 Perturbation Theory
AB 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 abilityto enhance the maximal effect of tritiated N-propylapomorphine ([3H]-NPA) at D2 receptors (D2R). In thisseries, 2-furoyl-L-leucylglycinamide (6a) produced a statistically significant increase in the maximal [3H]-NPAresponse at 10 pM (11 ± 1%), comparable to the effect of MIF-1 (22 ± 9%) at the same concentration. Thisresult supports previous evidence that the replacement of proline residue by heteroaromatic scaffolds aretolerated at the allosteric binding site of MIF-1. Biological assays performed for peptidomimetic 6a usingcortex 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 makesthis peptidomimetic a potential lead compound for further development and optimization, paving the way forthe 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 preclinicalassays, to seek a general model to assess the potential of a series of compounds as allosteric modulators for amyriad of receptors targets, organisms, cell lines, and biological activity parameters based on PerturbationTheory (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, ALLOPTML is the first general-purpose chemoinformatic toolusing a PTML-based model for the multi-output and multi-condition prediction of allosteric compounds, whichis expected to save both time and resources during the early drug discovery.
PB American Chemical Society
YR 2021
FD 2021
LK http://hdl.handle.net/10347/32607
UL http://hdl.handle.net/10347/32607
LA eng
NO Sampaio-Dias, Ivo; Rodríguez Borges, José; Yáñez-Pérez, Víctor... et al. Synthesis, Pharmacological and Biological Evaluation of 2- Furoyl-based MIF-1 Peptidomimetics, and the Development of a General-Purpose Model for Allosteric Modulators (ALLOPTML), ACS Chem. Neurosci. 2021, 12, 1, 203–215
NO 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
NO This research was funded by Fundação para a Ciência e Tecnologia (FCT, Portugal), through grantsUIDB/50006/2020 (to LAQV-REQUIMTE Research Unit) and for project grants PTDC/BIA-MIB/29059/2017and PEst-OE/QUI/UI0674/2013. This work was also supported by the Collaborative Project of Genomic DataIntegration (CICLOGEN). The authors thank the USEF Drug Screening Platform at University of Santiago deCompostela the support to carry out this work and also acknowledge the support of Ikerbasque, BasqueFoundation for Science and the research grants from Ministry of Economy and Competitiveness, MINECO,Spain (FEDER CTQ2016-74881-P) and Basque government (IT1045-16). IESD also thanks FCT for thedoctoral grant SFRH/BD/93632/2013 and XGM thanks Xunta de Galicia for financial funding with referenceGPC2014/003.
DS Minerva
RD 24 abr 2026