Rational Design of Novel Estrogen Receptor Antagonists

新型雌激素受体拮抗剂的合理设计

• 批准号: 7020036
• 负责人: DONALD J ABRAHAM
• 金额: $ 30.03万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7020036
• 关键词: X ray crystallography; chemical models; chemical structure function; computer simulation; cytotoxicity; drug design /synthesis /production; drug screening /evaluation; estrogen inhibitor; estrogen receptors; fluorescent dye /probe; isoquinolines; protein isoforms; receptor binding; tissue /cell culture; transfection; yeast two hybrid system

DESCRIPTION (provided by applicant): The main objective of this proposal is to develop and optimize novel and pure estrogen-receptor (ER) subtype alpha antagonists. Despite significant efforts in this area, there is an unmet need for developing selective ER antagonists. Some of our originally submitted research goals have been accomplished and lay a solid foundation for our revised proposal. Our proposal involves a multidisciplinary approach that combines expertise in organic synthesis, molecular biology, X-ray crystallography, and molecular modeling to rationally design and optimize ligands that are pure antagonists of estrogen receptors. Our specific aims include: (1) Synthesis of selective ER alpha antagonists: The new proposed molecules will be synthesized for lead optimization, enhancement of potency and selectivity of binding affinity at the receptor level. Such a comprehensive synthesis program should significantly increase our understanding for structure-activity relationships of the new tetrahydroisoquinoline scaffold; (2) X-ray crystallographic analysis of estrogen antagonists: In collaboration with Dr. F. Rastinejad (UVA), x-ray analyses of co-crystals of most potent ligands bound to the estrogen receptor will be used to explore ligand binding and to identify structural features necessary for pure antagonist activity; (3) Computational studies to enhance and guide lead optimization: Molecular modeling methods will be used to develop new drug design strategies as the results unfold and quantitate structure activity relationships (SAR); (4) In vitro and whole cell assays to screen ligands for estrogen receptor antagonism and estrogen receptor selectivity: Various assays such as a chemiluminescence, fluorescence-based competitive binding, a transient transfection reporter, a yeast two hybrid and a cell proliferation assay will be used to evaluate the agonist/antagonist activity and cytotoxicity of proposed compounds. A long-range goal of this proposal is to generate and optimize antiestrogens that are "pure" alpha-receptor antagonists.

描述(申请人提供)：这项建议的主要目标是开发和优化新的和纯的雌激素受体(ER)亚型阿尔法拮抗剂。尽管在这一领域做出了重大努力，但开发选择性ER拮抗剂的需求仍未得到满足。我们最初提交的一些研究目标已经完成，并为我们的修订方案奠定了坚实的基础。我们的建议涉及一种多学科的方法，结合有机合成、分子生物学、X射线结晶学和分子建模的专业知识，合理设计和优化作为雌激素受体纯拮抗剂的配体。 我们的具体目标包括：(1)选择性ERα拮抗剂的合成：将合成新的分子，用于在受体水平上进行先导优化、增强效力和结合亲和力的选择性。这样一个全面的合成计划将大大增加我们对新的四氢异喹啉支架结构-活性关系的了解；(2)雌激素拮抗剂的X射线结晶学分析：与F.Rastinejad博士(UVA)合作，将使用与雌激素受体结合的最有效配体的共晶体的X射线分析来探索配体结合，并确定纯拮抗剂活性所需的结构特征；(3)加强和指导主导优化的计算研究：随着结果的展开和结构活性关系(SAR)的量化，将使用分子建模方法开发新的药物设计策略；(4)体外和全细胞实验筛选雌激素受体拮抗剂和雌激素受体选择性配体：采用化学发光法、基于荧光的竞争结合法、瞬时转染法、酵母双杂交法和细胞增殖实验等方法评价所合成化合物的激动剂/拮抗剂活性和细胞毒性。 这项提议的一个长期目标是产生和优化抗雌激素，这些抗雌激素是“纯粹的”阿尔法受体拮抗剂。