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: 7174671
• 负责人: Martin K Safo
• 金额: $ 29.16万
• 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 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174671
• 关键词: Address; Adverse effects; Affinity; Agonist; Amides; Area; Binding; Biological Assay; Breast Cancer Cell; Cancer cell line; Cell Proliferation; Cells; Collaborations; Competitive Binding; Crystallization; Development; Dimerization; Drug Design; Drug usage; Elements; Entropy; Enzymes; Escherichia coli; Estradiol; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Fluorescence; Foundations; Goals; Human; Hydroxyl Radical; In Vitro; Laboratories; Lead; Length; Ligand Binding; Ligands; MCF7 cell; Methods; Modification; Molecular; Molecular Biology; Muscle Rigidity; NCOA3 gene; Numbers; Organic Synthesis; Protein Overexpression; Published Comment; Raloxifene; Range; Reporter; Research; Research Personnel; Resistance development; Roentgen Rays; Screening procedure; Side; Solid; Source; Structure-Activity Relationship; System; Tamoxifen; Testing; Tetrahydroisoquinolines; Transfection; Two-Hybrid System Techniques; X-Ray Crystallography; Yeasts; amino group; base; carbene; computer studies; cytotoxicity; design; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; hydroxyl group; in vitro Assay; insight; interdisciplinary approach; molecular modeling; mutant; novel; programs; receptor; receptor binding; scaffold; stem; 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（由申请人提供）：该提案的主要目的是开发和优化新颖和纯净的雌激素受体（ER）亚型α拮抗剂。尽管在这一领域做出了巨大的努力，但仍未满足发展选择性ER拮抗剂的需求。我们最初提交的研究目标已经实现，并为我们的修订建议奠定了坚实的基础。我们的建议涉及一种多学科方法，该方法结合了有机合成，分子生物学，X射线晶体学和分子建模的专业知识，以合理设计并优化雌激素受体的纯拮抗剂的配体。 我们的具体目的包括：（1）选择性ERα拮抗剂的合成：新提出的分子将被合成，以在受体水平上的铅优化，增强效力和结合亲和力的选择性。这样的全面合成计划应大大提高我们对新四氢异喹啉支架的结构活性关系的理解。 （2）雌激素拮抗剂的X射线晶体学分析：与F. Rastinejad（UVA）合作，对雌激素受体的最有效配体的共结晶的X射线分析将用于探索配体结合并识别纯拮抗剂活性所必需的结构特征； （3）增强和指导铅优化的计算研究：随着结果的展开并定量结构活动关系（SAR），分子建模方法将用于制定新的药物设计策略； (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. 该提案的一个远程目标是生成和优化“纯”α受体拮抗剂的抗雌激素。