PTML Computational Study, Synthesis, and Pharmacological Assay of MIF-1 Peptidomimetics

¹ LAQV/REQUIMTE, Dept. of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal.
² REQUIMTE/Department of Chemistry and Biochemistry, University of Porto, 4169-007 Porto, Portugal
³ Dept. of Pharmacology, Faculty of Medicine and Nursing, University of Basque Country (UPV-EHU), 48940 Leioa, Spain.
⁴ Department of Pharmacology, USC, 15782, Santiago de Compostela, Spain.
⁵ Department of Organic Chemistry, University of Santiago de Compostela (USC), 15782, Santiago de Compostela, Spain.
⁶ Department of Organic Chemistry II, University of the Basque Country (UPV/EHU), Biscay, Spain
⁷ IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain.

Published: 07 January 2021 by MDPI in MOL2NET'20, Conference on Molecular, Biomed., Comput. & Network Science and Engineering, 6th ed. congress CHEMBIOMOL-06: Chem. Biol. & Med. Chem. Workshop, Bilbao-Rostock, Germany-Galveston, Texas, USA, 2020

https://doi.org/10.3390/mol2net-06-08950 (registering DOI)

Abstract:

In a recent work we described the organic synthesis and experimental pharmacological assay of MIF-1 peptidomimetics modulators of D₂ receptors (D₂R). We measured their ability to enhance the maximal effect of tritiated N-propylapomorphine ([³H]-NPA) at D₂R. The 2-furoyl-l-leucylglycinamide (6a) showed increase maximal [³H]-NPA response at 10 pM (11 ± 1%) compared to MIF-1. Neurotoxicity assays of MIF-1 derivative 6a with cortex neurons of Wistar-Kyoto rat embryos suggest low neurotoxicity. Additionally, we reported a predictive model >20 000 outcomes of preclinical assays reported in ChEMBL for this kind of modulators. The model shows high specificity Sp = 89.2/89.4%, sensitivity Sn = 71.3/72.2%, and accuracy Ac = 86.1%/86.4% in training/validation series, respectively. The model is useful to predict this and similar compounds.

Ref: Synthesis, Pharmacological, and Biological Evaluation of 2-Furoyl-Based MIF-1 Peptidomimetics and the Development of a General-Purpose Model for Allosteric Modulators (ALLOPTML). Sampaio-Dias IE, Rodríguez-Borges JE, Yáñez-Pérez V, Arrasate S, Llorente J, Brea JM, Bediaga H, Viña D, Loza MI, Caamaño O, García-Mera X, González-Díaz H.ACS Chem Neurosci. 2021 Jan 6;12(1):203-215. doi: 10.1021/acschemneuro.0c00687. Epub 2020 Dec 21.PMID: 33347281

Keywords: MIF-1 peptidomimetics; D2R modulators; Organic synthesis; Neurotoxicity; Machine Learning

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