RT Journal Article
T1 Computer-aided design of multi-target ligands at A1R, A2AR and PDE10A, key proteins in neurodegenerative diseases
A1 Kalash, Leen
A1 Val García, Cristina
A1 Azuaje Guerrero, Jhonny Alberto
A1 Loza García, María Isabel
A1 Svensson, Fredrik
A1 Zoufir, Azedine
A1 Mervin, Lewis
A1 Ladds, Graham
A1 Brea Floriani, José Manuel
A1 Glen, Robert
A1 Sotelo Pérez, Eddy
A1 Bender, Andreas
K1 Multi-target ligands
K1 Adenosine receptor ligands
K1 PDE10A inhibitors
K1 Target prediction
K1 Drug design
K1 Docking
K1 QSAR
AB Compounds designed to display polypharmacology may have utility in treating complex diseases, where activity atmultiple targets is required to produce a clinical efect. In particular, suitable compounds may be useful in treatingneurodegenerative diseases by promoting neuronal survival in a synergistic manner via their multi-target activity atthe 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 feasibleligands that bind to A1 and A2A receptors and inhibit phosphodiesterase 10A (PDE10A), involving a retrosyntheticapproach employing in silico target prediction and docking, which may be generally applicable to multi-targetcompound design at several target classes. This approach has identifed 2-aminopyridine-3-carbonitriles as the frstmulti-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 asA1R/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 bothprotein 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 consideredfor further functional efcacy assessment, analog modifcation for the improvement of selectivity towards A1R, A2ARand PDE10A collectively, and evaluation of their potential synergy in modulating cAMP levels
PB BioMed Central
SN 1758-2946
YR 2017
FD 2017
LK http://hdl.handle.net/10347/19760
UL http://hdl.handle.net/10347/19760
LA eng
NO 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
NO LK thanks the IDB Cambridge International Scholarship for support. This workwas fnancially supported by the ERC Starting Grant to AB (No. 336159), theConsellería de Cultura, Educación e Ordenación Universitaria of the GalicianGovernment: (Grant: GPC2014/03), Centro singular de investigación de Galiciaaccreditation 2016–2019 (ED431G/09) and the European Regional Development Fund (ERDF)
DS Minerva
RD 24 abr 2026