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

Graham Ladds,Azedine Zoufir,María I Loza,Eddy Sotelo,Andreas Bender,José Brea,Fredrik Svensson,Cristina Val,Lewis Mervin,Jhonny Azuaje,Leen Kalash,Robert Glen

doi:10.1186/s13321-017-0249-4

Abstract

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 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 identified 2-aminopyridine-3-carbonitriles as the first 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 efficient 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 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 A1R, A2AR and PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels.

Highlights

Neurodegeneration involves the progressive loss of the structure and function of neurons, which is common in Parkinson’s, Huntington’s disease and schizophrenia [1]
We offer a computational strategy for designing synthetically feasible ligands that bind to A1 adenosine receptor (A1R) and A2A adenosine receptor (A2AR), and inhibit phosphodiesterase 10A (PDE10A)—a novel multi-target combination of G protein-coupled receptors (GPCRs) and an enzyme, which has not, to our knowledge, been previously exploited
Target prediction of the designed RECAP library To assess the likelihood of active compounds against A1R, A2AR and PDE10A, PIDGIN 1.0 (Prediction including Inactivity), a tool which uses ECFP 4 circular Morgan fingerprints and trained on ChEMBL actives and PubChem inactives, was used to perform in silico target prediction for the focused RECAP library (22,233 compounds) [24]

Summary

Introduction

Neurodegeneration involves the progressive loss of the structure and function of neurons, which is common in Parkinson’s, Huntington’s disease and schizophrenia [1]. Multi-target drugs work by creating a combination effect on multiple targets in the biological network simultaneously, which may (through e.g. synergistic effects) decrease the therapeutic dose required, increasing therapeutic efficacy, preventing drug resistance, and reducing target-related adverse effects [12,13,14]. Another advantage of multi-target drugs over other types of treatments such as combination therapies, is a reduced likelihood of drug–drug interactions [15, 16]

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