P6: RATIONAL DESIGN OF NOVEL NATURAL PRODUCT-DERIVED CANNABINOID LIGANDS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 对于这一提议，假设密集的基于配体的计算方法将产生更好的理解，以有效和选择性地抑制CB1/CB2，并将为新的CB配体的开发提供合理的指导。具体目标是：目的1.根据文献中已有的CB配体和活性数据，建立CB1和CB2激动剂和拮抗剂的四类药效团模型。药效团模型将进行交叉比较，以了解受体选择性的要求。目的2.使用AIM 1中最好的药效团模型进行虚拟筛选，以确定不同类别的新CB配体。 目的3.利用新型配体CB1和CB2的体外活性数据，建立定量构效关系(QSAR)模型，以帮助理解活性和选择性的分子基础，并为改进配体以提高活性和选择性提供合理的指导。 虽然在最初的提案中没有特别强调，但我们正在进行CB1和CB2受体三维结构的有限建模和配体对接研究，以帮助对AIMS 1和3进行基于配体的建模研究，并确保我们有尽可能全面的方法来合理寻找新的CB配体。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. For this proposal, the hypothesis is that intensive ligand-based computational methods will yield improved understanding of the requirements for effective and selective CB1/CB2 inhibition and will provide a rational guide for novel CB ligand development. The specific aims are: Aim 1. Develop four classes of pharmacophore models for CB1 and CB2 agonists and antagonists, based on all CB ligand and activity data available in the literature. The pharmacophore models will be cross-compared to gain understanding of requirements for receptor selectivity. Aim 2. Use the best pharmacophore models from Aim 1 for virtual screening to identify novel CB ligands in the different categories. Aim 3. Using CB1 and CB2 in vitro activity data for novel ligands, develop quantitative structure-activity relationship (QSAR) models to aid understanding of the molecular basis for the activity and selectivity and to provide a rational guide to modification of ligands for enhanced activity and selectivity. Though not specifically emphasized in the original proposal, we are proceeding with limited modeling of the CB1 and CB2 receptor three-dimensional structure and ligand docking studies, in order to aid the ligand-based modeling studies of Aims 1 and 3 and to ensure that we have as comprehensive an approach as possible to the rational search for novel CB ligands.