RATIONAL DESIGN OF ANTISICKLING AGENTS

抗镰剂的合理设计

• 批准号: 6388665
• 负责人: Martin K Safo
• 金额: $ 8.85万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388665
• 关键词: X ray crystallography; allosteric site; aromatic hydrocarbon receptor; chemical binding; chemical structure function; computer simulation; drug design /synthesis /production; drug screening /evaluation; halogenation; halogens; hemoglobin; human tissue; hydrocarbons; organic chemicals; respiratory gas analyzer; sickle cell anemia; sickling inhibitor; spectrometry; stereochemistry; temperature jump

DESCRIPTION (Adapted from applicant's abstract) The applicant's career goal is to seek a research position in a reputable Institution. His primary goal would be to establish rigorous research programs involving structure-based drug design to find the origin, causes, treatment and prevention of tropical diseases, such as sickle cell anemia, malaria, and sleeping sickness. Furthermore, it is anticipated that molecular modeling techniques unique to the problems to be encountered will be developed to improve the efficiency of the drug development process. To reach these goals, would require considerable experience and skills in drug designing process. Therefore, under the direction of his mentor, he intends to initiate a career development research program involving rational development of compounds to treat sickle cell anemia. This would help him gain the necessary skills and experience to develop his career as an independent researcher. Below is a brief description of the proposal research. A group of halogenated aromatic compounds are known to bind to hemoglobin and show potential as antisickling agents. These compounds bind to the surface of the protein and may explain the antisickling properties. The long term-goal of this research project is to utilize the above information to design and develop stereospecific agents to bind with high affinity to the surface of the hemoglobin for more potent antisickling agents. In addition, both the T and R-state hemoglobins will be used to study structure-function activities. Therefore, the specific aims are: 1) determine and refine the crystal structures of the deoxygenated hemoglobin co-crystallized with halogenated aromatic acids; 2) determine and refine the crystal structures of carbonmonoxy hemoglobin bound with halogenated aromatic acid; 3) rational design of new stereospecific compounds to bind to known binding sites at the surface of the hemoglobin, and other newly identified binding sites; and 4) biological evaluation of the designed compounds for antisickling, antigelling and allosteric activities.

描述（改编自申请人的摘要）申请人的职业目标 是在信誉良好的机构中寻求研究职位。 他的首要目标是 建立严格的研究计划，涉及基于结构的药物设计 寻找热带疾病的起源、原因、治疗和预防，例如 如镰状细胞性贫血、疟疾和昏睡病。 此外，它是 预计分子建模技术对于解决问题是独一无二的 遇到问题就会开发出提高效率的药物 发展过程。 为了实现这些目标，需要大量 药物设计过程中的经验和技能。 因此，根据 在导师的指导下，他打算发起一项职业发展研究 涉及合理开发治疗镰状细胞的化合物的计划 贫血。 这将帮助他获得必要的技能和经验 作为一名独立研究员发展他的职业生涯。 下面是一个简单的描述 提案研究。 已知一组卤代芳香族化合物可与血红蛋白结合并 显示出作为抗镰化剂的潜力。 这些化合物与表面结合 蛋白质并可以解释抗镰化特性。 长期目标 该研究项目的目的是利用上述信息来设计和 开发立体特异性试剂以高亲和力与表面结合 血红蛋白是更有效的抗镰刀剂。 此外，T 和 R 态血红蛋白将用于研究结构功能活动。 因此，具体目标是：1）确定并精制晶体 脱氧血红蛋白与卤化物共结晶的结构 芳香酸； 2) 确定并精炼一碳氧的晶体结构 与卤代芳香酸结合的血红蛋白； 3）合理设计新品 立体特异性化合物与已知的表面结合位点结合 血红蛋白和其他新发现的结合位点； 4) 生物 评估设计的化合物的抗镰刀化、抗凝胶化和 变构活动。