Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Mol Pharmacol. 2013 Apr;83(4):759-69. doi: 10.1124/mol.112.083758. Epub 2012 Dec 19.
The study of P2X receptors has long been handicapped by a poverty of small-molecule tools that serve as selective agonists and antagonists. There has been progress, particularly in the past 10 years, as cell-based high-throughput screening methods were applied, together with large chemical libraries. This has delivered some drug-like molecules in several chemical classes that selectively target P2X1, P2X3, or P2X7 receptors. Some of these are, or have been, in clinical trials for rheumatoid arthritis, pain, and cough. Current preclinical research programs are studying P2X receptor involvement in pain, inflammation, osteoporosis, multiple sclerosis, spinal cord injury, and bladder dysfunction. The determination of the atomic structure of P2X receptors in closed and open (ATP-bound) states by X-ray crystallography is now allowing new approaches by molecular modeling. This is supported by a large body of previous work using mutagenesis and functional expression, and is now being supplemented by molecular dynamic simulations and in silico ligand docking. These approaches should lead to P2X receptors soon taking their place alongside other ion channel proteins as therapeutically important drug targets.
对 P2X 受体的研究长期以来一直受到缺乏选择性激动剂和拮抗剂的小分子工具的阻碍。随着基于细胞的高通量筛选方法的应用以及大型化学文库的出现，这种情况在过去 10 年中取得了一些进展。这提供了一些具有药物样特性的分子，它们可以选择性地靶向 P2X1、P2X3 或 P2X7 受体。其中一些分子目前或曾经在类风湿性关节炎、疼痛和咳嗽的临床试验中。目前的临床前研究项目正在研究 P2X 受体在疼痛、炎症、骨质疏松症、多发性硬化症、脊髓损伤和膀胱功能障碍中的作用。X 射线晶体学确定 P2X 受体在关闭和开放（ATP 结合）状态下的原子结构，现在允许通过分子建模采用新方法。这得到了大量先前使用突变和功能表达的工作的支持，现在正在通过分子动力学模拟和计算机配体对接进行补充。这些方法应该会导致 P2X 受体很快与其他离子通道蛋白一起成为治疗上重要的药物靶点。
