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

• Published in: Journal of cheminformatics 2017-12, Vol.9 (1), p.1-19, Article 67
• Main Authors: Kalash, Leen, Val, Cristina, Azuaje, Jhonny, Loza, María I., Svensson, Fredrik, Zoufir, Azedine, Mervin, Lewis, Ladds, Graham, Brea, José, Glen, Robert, Sotelo, Eddy, Bender, Andreas
• Format: Article
• Language: English
• Subjects: Adenosine A2A receptors; Adenosine receptor ligands; CAD; Chemistry; Chemistry and Materials Science; Computational Biology/Bioinformatics; Computational chemistry; Computer aided design; Computer Applications in Chemistry; Computer simulation; Computer-generated environments; Cyclic AMP; Degeneration; Design; Docking; Documentation and Information in Chemistry; Drug design; Identification and classification; Ligands; Ligands (Biochemistry); Methods; Multi-target ligands; Nervous system; Neurodegenerative diseases; Neurological diseases; PDE10A inhibitors; Pharmacology; Phosphodiesterase; Protein families; Proteins; Receptors; Research Article; Selectivity; Synthesis; Target prediction; Theoretical and Computational Chemistry
• ISSN: 1758-2946; 1758-2946
• DOI: 10.1186/s13321-017-0249-4

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.