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Optimization of Adenosine 5′-Carboxamide Derivatives as Adenosine Receptor Agonists Using Structure-Based Ligand Design and Fragment Screening

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Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
§ University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, La Jolla, California 92093, United States
*For V.K.: phone, 858-784-7723; E-mail, [email protected]. For K.A.J.: phone, 301-496-9024; E-mail, [email protected]
Cite this: J. Med. Chem. 2012, 55, 9, 4297–4308
Publication Date (Web):April 9, 2012
Copyright © 2012 American Chemical Society

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    Abstract Image

    Structures of G protein-coupled receptors (GPCRs) have a proven utility in the discovery of new antagonists and inverse agonists modulating signaling of this important family of clinical targets. Applicability of active-state GPCR structures to virtual screening and rational optimization of agonists, however, remains to be assessed. In this study of adenosine 5′ derivatives, we evaluated the performance of an agonist-bound A2A adenosine receptor (AR) structure in retrieval of known agonists and then employed the structure to screen for new fragments optimally fitting the corresponding subpocket. Biochemical and functional assays demonstrate high affinity of new derivatives that include polar heterocycles. The binding models also explain modest selectivity gain for some substituents toward the closely related A1AR subtype and the modified agonist efficacy of some of these ligands. The study suggests further applicability of in silico fragment screening to rational lead optimization in GPCRs.

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    Known A2AAR agonists used in the initial docking model assessments. 3D binding models and scores for all ligands in Table 1. Synthetic procedures for the nucleoside derivatives and their characterization. This material is available free of charge via the Internet at

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    9. Lingyu Zhong, Qiao Peng, Xun Zeng. The role of adenosine A1 receptor on immune cells. Inflammation Research 2022, 71 (10-11) , 1203-1212.
    10. Heather Leduc‐Pessah, Cynthia Xu, Churmy Y. Fan, Rebecca Dalgarno, Yuta Kohro, Sydney Sparanese, Nikita N. Burke, Kenneth A. Jacobson, Christophe Altier, Daniela Salvemini, Tuan Trang. Spinal A 3 adenosine receptor activation acutely restores morphine antinociception in opioid tolerant male rats. Journal of Neuroscience Research 2022, 100 (1) , 251-264.
    11. Flavio Ballante, Albert J Kooistra, Stefanie Kampen, Chris de Graaf, Jens Carlsson, . Structure-Based Virtual Screening for Ligands of G Protein–Coupled Receptors: What Can Molecular Docking Do for You?. Pharmacological Reviews 2021, 73 (4) , 1698-1736.
    12. J. Daniel Hothersall, Andrew Y. Jones, Tim R. Dafforn, Trevor Perrior, Kathryn L. Chapman. Releasing the technical ‘shackles’ on GPCR drug discovery: opportunities enabled by detergent-free polymer lipid particle (PoLiPa) purification. Drug Discovery Today 2020, 25 (11) , 1944-1956.
    13. Kelton L. B. dos Santos, Jorddy N. Cruz, Luciane B. Silva, Ryan S. Ramos, Moysés F. A. Neto, Cleison C. Lobato, Sirlene S. B. Ota, Franco H. A. Leite, Rosivaldo S. Borges, Carlos H. T. P. da Silva, Joaquín M. Campos, Cleydson B. R. Santos. Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches. Molecules 2020, 25 (5) , 1245.
    14. Jinan Wang, Apurba Bhattarai, Waseem Imtiaz Ahmad, Treyton S. Farnan, Karen Priyadarshini John, Yinglong Miao. Computer-aided GPCR drug discovery. 2020, 283-293.
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    16. Pavel S. Nosik, Andrii S. Poturai, Mykola O. Pashko, Kostiantyn P. Melnykov, Sergey V. Ryabukhin, Dmitriy M. Volochnyuk, Oleksandr O. Grygorenko. N ‐Difluorocyclopropyl‐Substituted Pyrazoles: Synthesis and Reactivity. European Journal of Organic Chemistry 2019, 2019 (27) , 4311-4319.
    17. Giulia Rossetti, Achim Kless, Luhua Lai, Tiago F. Outeiro, Paolo Carloni. Investigating targets for neuropharmacological intervention by molecular dynamics simulations. Biochemical Society Transactions 2019, 47 (3) , 909-918.
    18. Rita C. Acúrcio, Anna Scomparin, Ronit Satchi‐Fainaro, Helena F. Florindo, Rita C. Guedes. Computer‐aided drug design in new druggable targets for the next generation of immune‐oncology therapies. WIREs Computational Molecular Science 2019, 9 (3)
    19. Pavel S. Nosik, Sergey V. Ryabukhin, Mykola O. Pashko, Galyna P. Grabchuk, Oleksandr O. Grygorenko, Dmitriy M. Volochnyuk. Synthesis of 1-hetaryl-2,2-difluorocyclopropane-derived building blocks: The case of pyrazoles. Journal of Fluorine Chemistry 2019, 217 , 80-89.
    20. Miles Congreve, Giles A. Brown, Alexandra Borodovsky, Michelle L. Lamb. Targeting adenosine A 2A receptor antagonism for treatment of cancer. Expert Opinion on Drug Discovery 2018, 13 (11) , 997-1003.
    21. Marian Vincenzi, Katarzyna Bednarska, Zbigniew Leśnikowski. Comparative Study of Carborane- and Phenyl-Modified Adenosine Derivatives as Ligands for the A2A and A3 Adenosine Receptors Based on a Rigid in Silico Docking and Radioligand Replacement Assay. Molecules 2018, 23 (8) , 1846.
    22. Antonella Ciancetta, Kenneth A. Jacobson. Breakthrough in GPCR Crystallography and Its Impact on Computer-Aided Drug Design. 2018, 45-72.
    23. Zhan-Guo Gao, Dilip K. Tosh, Shanu Jain, Jinha Yu, Rama R. Suresh, Kenneth A. Jacobson. A1 Adenosine Receptor Agonists, Antagonists, and Allosteric Modulators. 2018, 59-89.
    24. Stefania Baraldi, Pier Giovanni Baraldi, Paola Oliva, Kiran S. Toti, Antonella Ciancetta, Kenneth A. Jacobson. A2A Adenosine Receptor: Structures, Modeling, and Medicinal Chemistry. 2018, 91-136.
    25. Kenneth A. Jacobson, Dilip K. Tosh, Zhan-Guo Gao, Jinha Yu, Rama R. Suresh, Harsha Rao, Romeo Romagnoli, Pier Giovanni Baraldi, Mojgan Aghazadeh Tabrizi. Medicinal Chemistry of the A3 Adenosine Receptor. 2018, 169-198.
    26. Nicolas Diercxsens. 2,2-Difluoroethylamine. 2017, 1-4.
    27. Damian Bartuzi, Agnieszka Kaczor, Katarzyna Targowska-Duda, Dariusz Matosiuk. Recent Advances and Applications of Molecular Docking to G Protein-Coupled Receptors. Molecules 2017, 22 (2) , 340.
    28. M. Congreve, A. Bortolato, G. Brown, R.M. Cooke. Modeling and Design for Membrane Protein Targets. 2017, 145-188.
    29. Anirudh Ranganathan, David Rodríguez, Jens Carlsson. Structure-Based Discovery of GPCR Ligands from Crystal Structures and Homology Models. 2017, 65-99.
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    31. Punita Kumari, Eshan Ghosh, Arun K. Shukla. Emerging Approaches to GPCR Ligand Screening for Drug Discovery. Trends in Molecular Medicine 2015, 21 (11) , 687-701.
    32. Elizabeth Yuriev, Jessica Holien, Paul A. Ramsland. Improvements, trends, and new ideas in molecular docking: 2012–2013 in review. Journal of Molecular Recognition 2015, 28 (10) , 581-604.
    33. Giulia Rossetti, Domenica Dibenedetto, Vania Calandrini, Alejandro Giorgetti, Paolo Carloni. Structural predictions of neurobiologically relevant G-protein coupled receptors and intrinsically disordered proteins. Archives of Biochemistry and Biophysics 2015, 582 , 91-100.
    34. Jeremy Shonberg, Ralf C. Kling, Peter Gmeiner, Stefan Löber. GPCR crystal structures: Medicinal chemistry in the pocket. Bioorganic & Medicinal Chemistry 2015, 23 (14) , 3880-3906.
    35. Gengyang Yuan, Nicholas G Gedeon, Tanner C Jankins, Graham B Jones. Novel approaches for targeting the adenosine A 2A receptor. Expert Opinion on Drug Discovery 2015, 10 (1) , 63-80.
    36. Kenneth A. Jacobson, Zhan-Guo Gao, Silvia Paoletta, Evgeny Kiselev, Saibal Chakraborty, P. Suresh Jayasekara, Ramachandran Balasubramanian, Dilip K. Tosh. John Daly Lecture: Structure-guided Drug Design for Adenosine and P2Y Receptors. Computational and Structural Biotechnology Journal 2015, 13 , 286-298.
    37. Henrik Keränen, Hugo Gutiérrez-de-Terán, Johan Åqvist, . Structural and Energetic Effects of A2A Adenosine Receptor Mutations on Agonist and Antagonist Binding. PLoS ONE 2014, 9 (10) , e108492.
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    39. Stephen P. Andrews, Giles A. Brown, John A. Christopher. Structure‐Based and Fragment‐Based GPCR Drug Discovery. ChemMedChem 2014, 9 (2) , 256-275.
    40. Miles Congreve, João M. Dias, Fiona H. Marshall. Structure-Based Drug Design for G Protein-Coupled Receptors. 2014, 1-63.
    41. E F O'Donnell, D C Koch, W H Bisson, H S Jang, S K Kolluri. The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells. Cell Death & Disease 2014, 5 (1) , e1038-e1038.
    42. Albert J. Kooistra, Rob Leurs, Iwan J. P. de Esch, Chris de Graaf. From Three-Dimensional GPCR Structure to Rational Ligand Discovery. 2014, 129-157.
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    44. Kenneth A Jacobson. Crystal structures of the A2A adenosine receptor and their use in medicinal chemistry. In Silico Pharmacology 2013, 1 (1)
    45. András Visegrády, György M Keserű. Fragment-based lead discovery on G-protein-coupled receptors. Expert Opinion on Drug Discovery 2013, 8 (7) , 811-820.
    46. Sarah Barelier, Sarah E. Boyce, Inbar Fish, Marcus Fischer, David B. Goodin, Brian K. Shoichet, . Roles for Ordered and Bulk Solvent in Ligand Recognition and Docking in Two Related Cavities. PLoS ONE 2013, 8 (7) , e69153.
    47. Ramon Subirós‐Funosas, Lidia Nieto‐Rodriguez, Knud J. Jensen, Fernando Albericio. COMU: scope and limitations of the latest innovation in peptide acyl transfer reagents. Journal of Peptide Science 2013, 19 (7) , 408-414.
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    49. Vsevolod Katritch, Vadim Cherezov, Raymond C. Stevens. Structure-Function of the G Protein–Coupled Receptor Superfamily. Annual Review of Pharmacology and Toxicology 2013, 53 (1) , 531-556.
    50. Raymond C. Stevens, Vadim Cherezov, Vsevolod Katritch, Ruben Abagyan, Peter Kuhn, Hugh Rosen, Kurt Wüthrich. The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nature Reviews Drug Discovery 2013, 12 (1) , 25-34.
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    52. Kenneth A. Jacobson, Stefano Costanzi. New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors. Molecular Pharmacology 2012, 82 (3) , 361-371.

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