DESIGN AND DEVELOPMENT OF POTENTIAL ANTISICKLING AGENTS

这项研究计划的总体目标是延长我们的血红蛋白 研究和关注基于结构的药物发现：a）结构- 功能研究和作为抗缺血剂的变构效应物， B）抗弯/抗胶凝剂的设计和开发。 因此，我们的具体目标包括：（1）设计和合成 血红蛋白变构效应物以进一步建立结构特征 在调节变构的蛋白质中， 潜在的抗缺血药物;（2）氧平衡和动力学 反应的变构效应物的分析;（3）X射线晶体学 糖化血红蛋白变构效应物结构测定与优化 复合物，以提供关于a）氨基的运动的信息， B）水在变构转变过程中的作用; 变构探针的结合;和c）氨基的鉴定 酸残基是调节变构的关键， （4）合理设计和合成新的立体定向的 将特异性结合至 参与HbS聚合的目标残基;（5）X射线 晶体学研究，以确定HbA的结合位点- 效应复合物 这些将提供必要的原子细节， 合理重新设计分子以提高其功效;（6） 合成的分子用于抗剪切、抗胶凝的评价 和变构效应物活性。

The overall goal of this research program is to extend our hemoglobin studies and focus on structure based drug discovery in: a) Structure- Function studies and allosteric effectors as Anti-ischemic Agents and b) Design and Development of Antisickling/Antigelling Agents. Therefore our specific aims include: (1) Design and synthesis of hemoglobin allosteric effectors to further establish structural features within the protein that regulate allostery and can be developed as potential anti-ischemic agents; (2) Oxygen equilibrium and kinetic analyses of the reacted allosteric effectors; (3) X-ray crystallographic structure determination and refinement of HbA-allosteric effector complexes to provide information pertaining to a) the movements of amino acids during the allosteric transition; b) the role of water in the binding of the allosteric probes; and c) the identification of amino acid residues that are key to the regulation of the allosteric equilibrium; (4) rational design and synthesis of new stereospecific transient covalent antisickling agents that will specifically bind to target residues involved in the polymerization of HbS; (5) X-ray crystallographical studies to determine the binding sites of HbA- effector complexes. These will provide the atomic details necessary for rational re-design of molecules to increase their efficacy; (6) Evaluation of the synthesized molecules for antisickling, antigelling and allosteric effector activity by various methods.