Computer-aided design of multi-target ligands at A(1)R, A(2A)R and PDE10A, key proteins in neurodegenerative diseases
| Autor: | Graham Ladds, Eddy Sotelo, Jhonny Azuaje, Andreas Bender, Leen Kalash, Lewis H. Mervin, Fredrik Svensson, Cristina Val, María Isabel Loza, Robert C. Glen, Azedine Zoufir, José Brea |
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| Přispěvatelé: | Bender, Andreas [0000-0002-6683-7546], Apollo - University of Cambridge Repository, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares, Svensson, Fredrik [0000-0002-5556-8133], Mervin, Lewis [0000-0002-7271-0824], Ladds, Graham [0000-0001-7320-9612], Brea, José [0000-0002-5523-1979], Glen, Robert [0000-0003-1759-2914], Sotelo, Eddy [0000-0001-5571-2812] |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Quantitative structure–activity relationship Technology In silico Chemistry Multidisciplinary Computational biology Library and Information Sciences Drug design Docking lcsh:Chemistry 03 medical and health sciences PARKINSONS-DISEASE Target prediction SCHIZOPHRENIA Physical and Theoretical Chemistry Science & Technology Computer Science Information Systems lcsh:T58.5-58.64 Drug discovery Ligand lcsh:Information technology QSAR DERIVATIVES HIGHLY POTENT Phosphodiesterase Biological activity PDE10A inhibitors Multi-target ligands RECEPTOR ANTAGONISTS ADENOSINE Computer Graphics and Computer-Aided Design Computer Science Applications DRUG DISCOVERY Chemistry 030104 developmental biology lcsh:QD1-999 Docking (molecular) MULTICOMPONENT REACTIONS Physical Sciences Computer Science Adenosine receptor ligands Computer Science Interdisciplinary Applications PDE10A PHOSPHODIESTERASE 10A INHIBITORS BIOLOGICAL-ACTIVITY Research Article |
| Zdroj: | Journal of Cheminformatics, Vol 9, Iss 1, Pp 1-19 (2017) Minerva. Repositorio Institucional de la Universidad de Santiago de Compostela instname Journal of Cheminformatics |
| Popis: | Compounds 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 levels LK thanks the IDB Cambridge International Scholarship for support. This work was fnancially supported by the ERC Starting Grant to AB (No. 336159), the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (Grant: GPC2014/03), Centro singular de investigación de Galicia accreditation 2016–2019 (ED431G/09) and the European Regional Development Fund (ERDF) SI |
| Databáze: | OpenAIRE |
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