DESIGN AND DEVELOPMENT OF POTENTIAL ANTISICKLING AGENTS

这项研究的长期目标是发现潜在的 治疗镰状细胞性贫血的治疗剂，发展变构 治疗缺血性疾病和放射肿瘤学的血红蛋白抑制剂， 推进对小分子--大分子的基本认识 分子相互作用。研究领域的结合将继续 在我们的研究中广泛使用X射线结晶学和 发现铅分子和阐明铅分子的分子模拟技术 活性化合物在分子水平上的作用机理。这个 相应的分子将被合成，溶液和细胞 将进行研究，以评估体外活性和潜力 新分子的毒性问题。我们已经将一种化合物从 基础实验室研究到临床测试阶段，IND来自 美国食品和药物管理局。 我们的具体目标包括：前体药物的合成和检测 抗呕吐剂的类似物.其他芳香族化合物的合成和检验 醛及其衍生物，无毒原料或天然原料 作为潜在抗呕吐剂的产品；设计、合成和测试 新的血红蛋白变构调节剂；脱氧基的测定- 抗呕吐药物12C79(第一个)的Hb结合位点 治疗剂从血红蛋白的三维结构设计到 临床试验)和溶液结合测量.测定 活性抗晕剂和四种抗晕剂的溶液结合常数 血红蛋白变构效应剂的分类.测定 抗呕吐剂和变构抑制剂对氧解离的影响 血红蛋白溶液的曲线.溶液结合常数的比较 用变构抑制剂的P50值来确定是否 用蛋白质系统可以观察到内在活性；测定 活性分子的结合部位和相互作用 结晶学.正极和正极结合点的评价 使用新的计算机软件的负极性和疏水性相互作用 (提示)在前一提案中开发；进一步开发 HINT软件；活性化合物的流变效应的测量 红细胞.变构抑制剂和抗缺血剂的评价 在各种体外和体内系统和血液测量中 受试者的水平和血红蛋白反应的百分比。

The long range goals of this research are to discover a potential therapeutic agent to treat Sickle Cell anemia, develop allosteric inhibitors of hemoglobin for ischemic diseases and for radiation oncology, and to advance the fundamental understanding of small molecule - large molecule interactions. A combination of research fields will continue to be employed in our studies with extensive use of X-ray crystallographic and molecular modeling techniques to discover lead molecules and to elucidate mechanisms of action of active compounds at the molecular level. The corresponding molecules will be synthesized and solution and cellular studies will be conducted to evaluate the in vitro activity and potential toxicity problems of new molecules. We have advanced one compound from basic laboratory studies to the clinic testing phase with an IND from the FDA. Our specific aims include the: synthesis and testing of pro-drug like analogues of antisickling agents; synthesis and testing of other aromatic aldehydes and derivatives of non-toxic starting materials or natural products as potential antisickling agents; design, synthesize and testing of new allosteric modulators of hemoglobin; determination of the deoxy- incubated Hb binding sites for the antisickling drug 12C79 (the first therapeutic agent designed de novo from the 3D structure of hemoglobin to reach clinical trials) and solution binding measurements; determination of the solution binding constants of active antisickling agents and four classes of hemoglobin allosteric effectors; determination of the effects of antisickling agents and allosteric inhibitors on the oxygen dissociation curve of hemoglobin solutions; comparison of the solution binding constants with the P50 values for allosteric inhibitors to ascertain whether the intrinsic activity can be observed with a protein system; determination of the binding sites and interactions of active molecules crystallographically; evaluation of the binding sites for positive and negative polar and hydrophobic interactions using the new computer software (HINT) developed during the previous proposal; further development of the HINT software; measurement of the rheological effect of active compounds on erythrocytes; evaluation of allosteric inhibitors an anti-ischemic agents in a variety of in vitro and in vivo systems and measurement of blood levels and the % hemoglobin reaction in human subjects.