RATIONAL DESIGN OF ANTISICKLING AGENTS

描述（改编自申请人的摘要）申请人的职业目标 就是在一个有声望的机构里找一个研究职位 他的主要目标是 建立严格的研究计划，包括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， 镰状细胞性贫血疟疾和昏睡病 再者是 预计，分子建模技术独特的问题， 遇到的将被开发，以提高药物的效率 发展过程 为了实现这些目标，需要大量的 药物设计过程的经验和技能。 因此，根据 在导师的指导下，他打算发起一项职业发展研究 合理开发治疗镰状细胞病的化合物的计划 贫血 这将帮助他获得必要的技能和经验， 发展他的职业生涯作为一个独立的研究员。 下面是一个简短的描述 的提案研究。 已知一组卤代芳族化合物与血红蛋白结合， 显示出作为抗弯剂潜力。 这些化合物结合到 蛋白质，并可能解释抗锯齿性能。 长期目标 本研究计划的目的是利用上述信息设计和 开发立体特异性试剂，以高亲和力结合到 血红蛋白用于更有效的抗凝血剂。 此外，T和 R-状态血红蛋白将用于研究结构-功能活性。 因此，本研究的具体目标是：1）确定和细化晶体 脱氧血红蛋白的结构与卤化的共结晶 芳香酸; 2）确定和精炼碳一氧的晶体结构 血红蛋白与卤代芳香酸结合; 3）合理设计新的 立体特异性化合物结合到膜表面的已知结合位点， 血红蛋白和其他新鉴定的结合位点;以及4）生物学 评价设计的抗剪切、抗胶凝和 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.