Kalash, LeenVal García, CristinaAzuaje Guerrero, Jhonny AlbertoLoza García, María IsabelSvensson, FredrikZoufir, AzedineMervin, LewisLadds, GrahamBrea Floriani, José ManuelGlen, RobertSotelo Pérez, EddyBender, Andreas2019-09-112019-09-112017Kalash, 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/s13321-017-0249-41758-2946http://hdl.handle.net/10347/19760Compounds 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 levelseng© 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 statedAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Multi-target ligandsAdenosine receptor ligandsPDE10A inhibitorsTarget predictionDrug designDockingQSARjournal article10.1186/s13321-017-0249-4open access