The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
Structure-Based Discovery of A 2A Adenosine Receptor Ligands
Open accessAbstract
The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A(2A) adenosine receptor, based on complementarity to its recently determined structure. The A(2A) adenosine receptor signals in the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases. We used molecular docking to screen a 1.4 million compound database against the X-ray structure computationally and tested 20 high-ranking, previously unknown molecules experimentally. Of these 35% showed substantial activity with affinities between 200 nM and 9 microM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A(2A) versus the related A(1) and A(3) subtypes. These high hit rates and affinities at least partly reflect the bias of commercial libraries toward GPCR-like chemotypes, an issue that we attempt to investigate quantitatively. Despite this bias, many of the most potent new ligands were novel, dissimilar from known ligands, providing new lead structures for modulation of this medically important target.
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Cites
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Self-citationA model binding site for testing scoring functions in molecular docking.
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Sterling, T., & Irwin, J. J. (2015) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5b00559 · Cited by 3,224
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Mysinger, M. M., Carchia, M., Irwin, J. J., & Shoichet, B. K. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm300687e · Cited by 2,412
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Virtual discovery of melatonin receptor ligands to modulate circadian rhythms
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Self-citationStructures of the σ2 receptor enable docking for bioactive ligand discovery
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Self-citationDiscovery of new GPCR ligands to illuminate new biology
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Metadata
- Authors
- Carlsson, J., Yoo, L., Gao, Z.-G., Irwin, J. J., Shoichet, B. K., & Jacobson, K. A.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-04-20
- Volume
- 53
- Issue
- 9
- Pages
- 3748-3755
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2122434726
- Cited by
- 227
- References
- 5
- FWCI
- 26.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
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