Journal
CHEMMEDCHEM
Volume 15, Issue 21, Pages 1958-1973Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000465
Keywords
drug discovery; molecular modeling; nucleosides; nucleotides; receptors
Categories
Funding
- NIDDK Intramural Research Program [ZIADK31116, ZIADK31117, ZIADK31126]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [ZIADK031116, ZIADK031117, ZIADK031126] Funding Source: NIH RePORTER
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The purinergic signaling system includes membrane-bound receptors for extracellular purines and pyrimidines, and enzymes/transporters that regulate receptor activation by endogenous agonists. Receptors include: adenosine (A(1), A(2A), A(2B,)and A(3)) and P2Y (P2Y(1), P2Y(2), P2Y(4), P2Y(6), P2Y(11), P2Y(12), P2Y(13), and P2Y(14)) receptors (all GPCRs), as well as P2X receptors (ion channels). Receptor activation, especially accompanying physiological stress or damage, creates a temporal sequence of signaling to counteract this stress and either mobilize (P2Rs) or suppress (ARs) immune responses. Thus, modulation of this large signaling family has broad potential for treating chronic diseases. Experimentally determined structures represent each of the three receptor families. We focus on selective purinergic agonists (A(1), A(3)), antagonists (A(3), P2Y(14)), and allosteric modulators (P2Y(1), A(3)). Examples of applying structure-based design, including the rational modification of known ligands, are presented for antithrombotic P2Y(1)R antagonists and anti-inflammatory P2Y(14)R antagonists and A(3)AR agonists. A(3)AR agonists are a potential, nonaddictive treatment for chronic neuropathic pain.
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