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Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity at multiple targets is required to produce a clinical effect. 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 A 1  and A 2A  receptors (A 1 R and A 2A R) 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 A 1  and A 2A  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 identified 2-aminopyridine-3-carbonitriles as the first multi-target ligands at A 1 R, A 2A R and PDE10A, by showing agreement between the ligand and structure based predictions at these targets. The series were synthesized via an efficient one-pot scheme and validated pharmacologically as A 1 R/A 2A R–PDE10A ligands, with IC 50  values of 2.4–10.0 μM at PDE10A and K i  values of 34–294 nM at A 1 R and/or A 2A R. Furthermore, selectivity profiling 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 off-targets. In addition, both compounds  8  and  16  exhibited the desired multi-target profile, which could be considered for further functional efficacy assessment, analog modification for the improvement of selectivity towards A 1 R, A 2A R and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.Electronic supplementary material  The online version of this article (10.1186/s13321-017-0249-4) contains supplementary material, which is available to authorized users.

Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases