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Molecular Modeling and Reengineering of A3 Adenosine Receptors

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A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics

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Abstract

The development of ligands for the A3 adenosine receptor (AR) has been directed mainly by traditional medicinal chemistry, but the influence of structure-based approaches is increasing. Rhodopsin-based homology modeling had been used for many years to obtain three-dimensional models of the A3AR, and different A3AR models have been published describing the hypothetical interactions with known A3AR ligands having different chemical scaffolds. The recently published structure of the human A2AAR provides a new template for GPCR modeling, however even use of the A2AAR as a template for modeling other AR subtypes is still imprecise. The models compared here are based on bovine rhodopsin, the human β2-adrenergic receptor, and the A2AAR as templates. The sequence of the human A3AR contains only one cysteine residue (Cys166) in the second extracellular loop (EL2), which putatively forms a conserved disulfide bridge with the respective cysteine residues of TM3 (Cys83). Homology models of the A3AR have been helpful in providing structural hypotheses for the design of new ligands. Site-directed mutagenesis of the A3AR shows an important role in ligand recognition for specific residues in TM3, TM6 and TM7. The approach of neoceptors is a means of reengineering a given GPCR, such as the A3AR, to recognize a chemically tailored agonist ligand, and to no longer recognize the native agonist. It can serve to validate a molecular model, by establishing proximity of functional groups in the pair of neoceptor and its complementary tailored agonist ligand, assuming that this pair is pharmacologically orthogonal with respect to the native species. The neoceptor approach may also be useful in mechanistic elucidation and is projected for future use in gene therapy.

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Acknowledgements

Kenneth A Jacobson acknowledges support by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases.

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Authors and Affiliations

  1. Molecular Modeling Section (MMS), Department of Pharmaceutical Sciences, University of Padova, Via Marzolo, 5, 35131, Padova, Italy

    Stefano Moro & Erika Morizzo

  2. Molecular Recognition Section (MRS), Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Kenneth A. Jacobson

Authors
  1. Stefano Moro
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  2. Erika Morizzo
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  3. Kenneth A. Jacobson
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Corresponding author

Correspondence to Stefano Moro .

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Editors and Affiliations

  1. Ist. Farmacologia, Universita Ferrara, Via Fossato di Mortara 64 B, Ferrara, 44100, Italy

    Pier Andrea Borea

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Moro, S., Morizzo, E., Jacobson, K.A. (2010). Molecular Modeling and Reengineering of A3 Adenosine Receptors. In: Borea, P. (eds) A3 Adenosine Receptors from Cell Biology to Pharmacology and Therapeutics. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3144-0_8

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