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

P6：新型天然产物衍生的大麻素配体的合理设计

• 批准号: 8167946
• 负责人: Robert J Doerksen
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167946
• 关键词: Agonist; Biological Factors; CNR2 gene; Cannabinoids; Categories; Computer Retrieval of Information on Scientific Projects Database; Computing Methodologies; Data; Development; Docking; Ensure; Funding; Grant; Institution; Ligands; Literature; Modeling; Modification; Molecular; Quantitative Structure-Activity Relationship; Research; Research Personnel; Resources; Screening procedure; Source; Study models; United States National Institutes of Health; base; design; improved; in vitro activity; novel; pharmacophore; receptor; three dimensional structure; virtual

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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 对于这个建议，假设是，密集的配体为基础的计算方法将产生有效的和选择性的CB 1/CB 2抑制的要求，提高理解，并将提供一个合理的指导新的CB配体的发展。具体目标是：目标1。根据文献中可用的所有CB配体和活性数据，开发CB 1和CB 2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。 目标2.使用目标1中的最佳药效团模型进行虚拟筛选，以识别不同类别的新型CB配体。 目标3.使用CB 1和CB 2在体外活性数据的新配体，开发定量结构-活性关系（QSAR）模型，以帮助理解的活性和选择性的分子基础，并提供一个合理的指导，以提高活性和选择性的配体的修饰。 虽然在最初的提案中没有特别强调，但我们正在进行CB 1和CB 2受体三维结构和配体对接研究的有限建模，以帮助目标1和3的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。