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

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.

[1]  W. Whaley,et al.  SYNTHESIS OF ISOQUINOLINE DERIVATIVES , 1949 .

[2]  P. Molina,et al.  Synthesis of isoquinoline derivatives by a tandem aza-Wittig/electrocyclization strategy and preparation of the unknown 1,9-diazaphenalene ring by a consecutive electrocyclic ring closure/Claisen rearrangement/intramolecular amination process , 1990 .

[3]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[4]  T. Palmer,et al.  Adenosine receptors , 1995, Neuropharmacology.

[5]  Michael M. Hann,et al.  RECAP-Retrosynthetic Combinatorial Analysis Procedure: A Powerful New Technique for Identifying Privileged Molecular Fragments with Useful Applications in Combinatorial Chemistry , 1998, J. Chem. Inf. Comput. Sci..

[6]  Ming-tao Li,et al.  Cyclic AMP Promotes Neuronal Survival by Phosphorylation of Glycogen Synthase Kinase 3β , 2000, Molecular and Cellular Biology.

[7]  Eric Jones,et al.  SciPy: Open Source Scientific Tools for Python , 2001 .

[8]  S. Latini,et al.  Adenosine in the central nervous system: release mechanisms and extracellular concentrations , 2001, Journal of neurochemistry.

[9]  Sui Huang.  Rational drug discovery: what can we learn from regulatory networks? , 2002, Drug discovery today.

[10]  L. Weber.  The application of multi-component reactions in drug discovery. , 2002, Current medicinal chemistry.

[11]  Ping Chen,et al.  Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity. , 2004, Journal of medicinal chemistry.

[12]  Hege S. Beard,et al.  Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. , 2004, Journal of medicinal chemistry.

[13]  Richard Morphy,et al.  From magic bullets to designed multiple ligands. , 2004, Drug discovery today.

[14]  J. Obeso,et al.  Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough , 2004, The Lancet Neurology.

[15]  M. Loza,et al.  Synthesis and biological activity of new potential agonists for the human adenosine A2A receptor. , 2004, Journal of medicinal chemistry.

[16]  A. Christopoulos,et al.  Fitting Models to Biological Data Using Linear and Nonlinear Regression: A Practical Guide to Curve Fitting , 2004 .

[17]  Péter Csermely,et al.  The efficiency of multi-target drugs: the network approach might help drug design. , 2004, Trends in pharmacological sciences.

[18]  V. Yardley,et al.  Application of multicomponent reactions to antimalarial drug discovery. Part 2: New antiplasmodial and antitrypanosomal 4-aminoquinoline gamma- and delta-lactams via a 'catch and release' protocol. , 2006, Bioorganic & medicinal chemistry.

[19]  Jeremy R. Greenwood,et al.  Epik: a software program for pKa prediction and protonation state generation for drug-like molecules , 2007, J. Comput. Aided Mol. Des..

[20]  B. Neustadt,et al.  Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines. , 2007, Bioorganic & medicinal chemistry letters.

[21]  S. Moro,et al.  Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: Effect of the N-5 bond type on the affinity and selectivity at the four adenosine receptor subtypes , 2007, Purinergic Signalling.

[22]  R. Stevens,et al.  The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist , 2008, Science.

[23]  R. D. Williams,et al.  Preclinical Characterization of Selective Phosphodiesterase 10A Inhibitors: A New Therapeutic Approach to the Treatment of Schizophrenia , 2008, Journal of Pharmacology and Experimental Therapeutics.

[24]  A. IJzerman,et al.  2-Amino-6-furan-2-yl-4-substituted nicotinonitriles as A2A adenosine receptor antagonists. , 2008, Journal of medicinal chemistry.

[25]  A. Abadi,et al.  Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors. , 2009, Bioorganic & medicinal chemistry.

[26]  G. Bernardi,et al.  Phosphodiesterase 10 inhibition reduces striatal excitotoxicity in the quinolinic acid model of Huntington's disease , 2009, Neurobiology of Disease.

[27]  Charles L. Brooks,et al.  Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008 , 2009, Nature Reviews Drug Discovery.

[28]  Boon Chuan Low,et al.  In-Silico Approaches to Multi-target Drug Discovery , 2010, Pharmaceutical Research.

[29]  J. Baell,et al.  New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. , 2010, Journal of medicinal chemistry.

[30]  P. Jeffrey,et al.  Assessment of the blood–brain barrier in CNS drug discovery , 2010, Neurobiology of Disease.

[31]  Zhe Shi,et al.  Computer Aided Multi-target Drug Design, Multi-target Virtual Screening , 2010 .

[32]  A. Borisy,et al.  Adenosine A2A receptor agonists and PDE inhibitors: a synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies. , 2010, Blood.

[33]  J. Kehler,et al.  Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[34]  U. Egerland,et al.  Highly potent, selective, and orally active phosphodiesterase 10A inhibitors. , 2011, Journal of medicinal chemistry.

[35]  A. Drabczyńska,et al.  Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones. , 2011, European journal of medicinal chemistry.

[36]  Catarina Gomes,et al.  Adenosine receptors and brain diseases: neuroprotection and neurodegeneration. , 2011, Biochimica et biophysica acta.

[37]  Andreas Bender,et al.  From in silico target prediction to multi-target drug design: current databases, methods and applications. , 2011, Journal of proteomics.

[38]  X. García‐Mera,et al.  Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists. , 2011, Journal of medicinal chemistry.

[39]  E. Hu,et al.  Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors. , 2012, Bioorganic & medicinal chemistry letters.

[40]  Maria F. Sassano,et al.  Automated design of ligands to polypharmacological profiles , 2012, Nature.

[41]  Arun Siddharth Konagurthu,et al.  Super: a web server to rapidly screen superposable oligopeptide fragments from the protein data bank , 2012, Nucleic Acids Res..

[42]  R. Stevens,et al.  Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions , 2012, Science.

[43]  John P. Overington,et al.  ChEMBL: a large-scale bioactivity database for drug discovery , 2011, Nucleic Acids Res..

[44]  J. Safari,et al.  Ultrasound-promoted an efficient method for one-pot synthesis of 2-amino-4,6-diphenylnicotinonitriles in water: a rapid procedure without catalyst. , 2012, Ultrasonics sonochemistry.

[45]  A. Bender,et al.  Extensions to In Silico Bioactivity Predictions Using Pathway Annotations and Differential Pharmacology Analysis: Application to Xenopus laevis Phenotypic Readouts , 2013, Molecular informatics.

[46]  S. Sakkiah,et al.  An Innovative Strategy for Dual Inhibitor Design and Its Application in Dual Inhibition of Human Thymidylate Synthase and Dihydrofolate Reductase Enzymes , 2013, PloS one.

[47]  S. Sakkiah,et al.  Identification of Inhibitor Binding Site in Human Sirtuin 2 Using Molecular Docking and Dynamics Simulations , 2013, PloS one.

[48]  Woody Sherman,et al.  Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments , 2013, Journal of Computer-Aided Molecular Design.

[49]  J. Peters.  Polypharmacology - foe or friend? , 2013, Journal of medicinal chemistry.

[50]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[51]  Manuel de Lera Ruiz,et al.  Adenosine A2A receptor as a drug discovery target. , 2014, Journal of medicinal chemistry.

[52]  I. Amelio,et al.  Polypharmacology of small molecules targeting the ubiquitin–proteasome and ubiquitin-like systems , 2015, Oncotarget.

[53]  Thomas Sander,et al.  DataWarrior: An Open-Source Program For Chemistry Aware Data Visualization And Analysis , 2015, J. Chem. Inf. Model..

[54]  S. Kapur,et al.  Loss of phosphodiesterase 10A expression is associated with progression and severity in Parkinson's disease. , 2015, Brain : a journal of neurology.

[55]  A. Megens,et al.  Identification of a novel orally bioavailable phosphodiesterase 10A (PDE10A) inhibitor with efficacy in animal models of schizophrenia. , 2015, Journal of medicinal chemistry.

[56]  V. S. Lingam,et al.  Design, Synthesis, and Pharmacological Evaluation of 5,6-Disubstituted Pyridin-2(1H)-one Derivatives as Phosphodiesterase 10A (PDE10A) Antagonists. , 2015, Journal of medicinal chemistry.

[57]  Andreas Bender,et al.  Target prediction utilising negative bioactivity data covering large chemical space , 2015, Journal of Cheminformatics.

[58]  Nisachon Khunnawutmanotham,et al.  Divergent Total Syntheses to Azafluoranthene and Dehydroaporphine Alkaloids. , 2015 .

[59]  Olivier Sperandio,et al.  FAF-Drugs3: a web server for compound property calculation and chemical library design , 2015, Nucleic Acids Res..

[60]  Mahbobeh Zadpour,et al.  Iron(III) phosphate as a green and reusable catalyst for the synthesis of 4,6-disubstituted 2-aminopyridine-3-carbonitriles , 2015, Monatshefte für Chemie - Chemical Monthly.

[61]  Zhiyong Lu,et al.  The CHEMDNER corpus of chemicals and drugs and its annotation principles , 2015, Journal of Cheminformatics.

[62]  Nisachon Khunnawutmanotham,et al.  Divergent Total Syntheses to Azafluor­anthene and Dehydroaporphine Alkaloids , 2015 .

[63]  Muhammad Khan,et al.  Targeting Apoptosis and Multiple Signaling Pathways with Icariside II in Cancer Cells , 2015, International journal of biological sciences.

[64]  G. McGaughey,et al.  Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis. , 2015, Journal of medicinal chemistry.

[65]  M. Zolfigol,et al.  Retraction: Experimental and theoretical studies of the nanostructured {Fe3O4@SiO2@(CH2)3Im}C(CN)3 catalyst for 2-amino-3-cyanopyridine preparation via an anomeric based oxidation , 2016, RSC advances.

[66]  S. Meegalla,et al.  Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors. , 2016, Bioorganic & medicinal chemistry letters.

[67]  A. T. Nguyen,et al.  Extracellular Loop 2 of the Adenosine A1 Receptor Has a Key Role in Orthosteric Ligand Affinity and Agonist Efficacy , 2016, Molecular Pharmacology.

[68]  W. Guba,et al.  A Real-World Perspective on Molecular Design. , 2016, Journal of medicinal chemistry.

[69]  Sally Wagner,et al.  Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted imidazo[1,5-a]quinoxalines. , 2016, European journal of medicinal chemistry.

[70]  Dominik Dolles,et al.  Aminobenzimidazoles and Structural Isomers as Templates for Dual‐Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders , 2016, ChemMedChem.

[71]  John B. O. Mitchell,et al.  Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies , 2016, Front. Neurosci..

[72]  A. Cavalli,et al.  Multitarget Drug Discovery and Polypharmacology , 2016, ChemMedChem.

[73]  T. Matsushima,et al.  Striatal and Tegmental Neurons Code Critical Signals for Temporal-Difference Learning of State Value in Domestic Chicks , 2016, Front. Neurosci..

[74]  M. Yoshikawa,et al.  Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket. , 2016, Bioorganic & medicinal chemistry.

[75]  John D. Schreier,et al.  Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia. , 2016, Bioorganic & medicinal chemistry letters.

[76]  G. Ladds,et al.  Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity. , 2016, Journal of medicinal chemistry.

[77]  D. Khalili.  Graphene oxide: a reusable and metal-free carbocatalyst for the one-pot synthesis of 2-amino-3-cyanopyridines in water , 2016 .

[78]  A. IJzerman,et al.  Controlling the Dissociation of Ligands from the Adenosine A2A Receptor through Modulation of Salt Bridge Strength. , 2016, Journal of medicinal chemistry.