Traditional Chinese Herbs as Probes of P2X Receptors and other Ion Channels in the Pain Pathway

离子通道作为药物靶点。离子通道是一类重要的药物靶点。所有批准的药物中约13%靶向配体门控和电压门控离子通道（Overington，Al-Lazikani等人，2006年）。在广泛的全基因组测序的推动下，越来越多的离子通道基因突变被发现与越来越多的疾病有关。在这个项目中，我们希望再次筛选出常用的中药，以对抗尽可能多的疼痛通路的离子通道。我们将从离子通道结构和中药成分的化学结构两个方面解释数据，以开发可检验的假设：（i）中药成分结合的确切位置，以及（ii）离子通道对配体的最佳分子识别需要哪些分子特征？我们将使用药效团模型，以确定潜在的配体在化学数据库中的虚拟筛选和突变离子通道的结构指导的基础上，以验证预测的作用位点。尽管经过数十年的研究，仍然需要易于处理，有效发挥作用的止痛药，这些止痛药具有良好的耐受性，不会导致成瘾，也不会导致心血管或血液毒性。该项目有可能在这方面提供宝贵的见解。

Ion channels as drug targets. Ion channels are an important class of drug targets. About 13 % of all approved drugs target ligand-gated and voltage-gated ion channels (Overington, Al-Lazikani et al., 2006). Fostered by the widespread whole genome sequencing, an increasing number of mutations in ion channel genes are found to be linked with an increasing number of diseases. With this project, we want to screen TCMs commonly used again all forms of pain against as many ion channels of the pain pathway as possible. We will interpret the data both in regard of the ion channel structure and the chemical structure of the TCM ingredient to develop testable hypotheses (i) where exactly in the identified channel the TCMs ingredient binds and (ii) which molecular features are necessary for optimal molecular recognition of the ligand by the ion channel? We will use pharmacophore models to identify potential ligands in chemical databases by virtual screening and mutate ion channels on a structure-guided basis to verify predicted sites of action. Despite decades of research, there is an ongoing need for easily to handle, efficiently acting pain remedies that are well tolerated and neither lead to addiction nor cardiovascular or blood toxicity. This project has the potential to provide valuable insights in this respect.