Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases
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Título: | Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases
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Autor/a: | Kalash, Leen
Val García, Cristina
Azuaje Guerrero, Jhonny Alberto
Loza García, María Isabel
Svensson, Fredrik
Zoufir, Azedine
Mervin, Lewis
Ladds, Graham
Brea Floriani, José Manuel
Glen, Robert
Sotelo Pérez, Eddy
Bender, Andreas
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Centro/Departamento: | Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares
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Palabras chave: | Multi-target ligands | Adenosine receptor ligands | PDE10A inhibitors | Target prediction | Drug design | Docking | QSAR | |
Data: | 2017
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Editor: | BioMed Central
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Cita bibliográfica: | Kalash, L., Val, C., Azuaje, J., Loza, M., Svensson, F., & Zoufir, A. et al. (2017). Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases. Journal Of Cheminformatics, 9(1). doi: 10.1186/s13321-017-0249-4
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Resumo: | Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at
multiple targets is required to produce a clinical efect. In particular, suitable compounds may be useful in treating
neurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity at
the adenosine A1 and A2A receptors (A1R and A2AR) and phosphodiesterase 10A (PDE10A), which modulate intracellular cAMP levels. Hence, in this work we describe a computational method for the design of synthetically feasible
ligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosynthetic
approach employing in silico target prediction and docking, which may be generally applicable to multi-target
compound design at several target classes. This approach has identifed 2-aminopyridine-3-carbonitriles as the frst
multi-target ligands at A1R, A2AR and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efcient one-pot scheme and validated pharmacologically as
A1R/A2AR–PDE10A ligands, with IC50 values of 2.4–10.0 μM at PDE10A and Ki
values of 34–294 nM at A1R and/or A2AR.
Furthermore, selectivity profling of the synthesized 2-amino-pyridin-3-carbonitriles against other subtypes of both
protein families showed that the multi-target ligand 8 exhibited a minimum of twofold selectivity over all tested oftargets. In addition, both compounds 8 and 16 exhibited the desired multi-target profle, which could be considered
for further functional efcacy assessment, analog modifcation for the improvement of selectivity towards A1R, A2AR
and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels |
Versión do editor: | https://doi.org/10.1186/s13321-017-0249-4 |
URI: | http://hdl.handle.net/10347/19760
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DOI: | 10.1186/s13321-017-0249-4 |
ISSN: | 1758-2946
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Dereitos: | © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Atribución 4.0 Internacional
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