RATIONAL DESIGN OF ANTISICKLING AGENTS

描述(摘自申请者的摘要)申请者的职业目标 就是在一家声誉卓著的机构寻求一个研究职位。他的主要目标将是 建立严谨的研究计划，涉及基于结构的药物设计，以 寻找热带疾病的起源、病因、治疗和预防，如 如镰状细胞性贫血、疟疾和昏睡病。此外，它是 预计分子建模技术是独一无二的问题 将遇到的药物开发为提高效率的药物 发展进程。要实现这些目标，需要相当多的资金 在药物设计过程中的经验和技能。因此，在 在导师的指导下，他打算发起一项职业发展研究 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，以 发展他作为一名独立研究员的职业生涯。下面是简短的描述 提案研究的一部分。 已知一组卤代芳香化合物与血红蛋白和 显示出作为抗呕吐剂的潜力。这些化合物结合在…的表面上 这是一种蛋白质，可能解释了它的抗病作用。长期目标 本研究项目的目的是利用上述信息来设计和 开发立体定向剂，以高亲和力结合到细胞表面 用于更有效的抗呕吐剂的血红蛋白。此外，T和T型 R态血红蛋白将被用于研究结构-功能活性。 因此，具体的目标是：1)测定和提纯晶体 脱氧血红蛋白与卤代共结晶的结构 芳香酸；2)测定和提纯一氧化碳的晶体结构 卤代芳香酸与血红蛋白的结合；3)合理设计新的 立体专一性化合物结合到表面的已知结合部位 血红蛋白和其他新发现的结合部位；以及4)生物 对设计的抗恶心、抗凝血和抗凝血化合物的评价 变构活性。

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.