Structure-Based Discovery of A2A Adenosine Receptor Ligands

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• 作者：Jens Carlsson ; Lena Yoo ; Zhan-Guo Gao ; John J. Irwin ; Brian K. Shoichet ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：May 13, 2010
• 年：2010
• 卷：53
• 期：9
• 页码：3748-3755
• 全文大小：903K
• 年卷期：v.53,no.9(May 13, 2010)
• ISSN：1520-4804

文摘

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 μM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A_2A versus the related A₁ and A₃ 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.