DESIGN AND DEVELOPMENT OF POTENTIAL ANTISICKLING AGENTS

这项研究的长期目标是发现一种潜在的 用于治疗镰状细胞性贫血的治疗剂， 用于缺血性疾病和放射肿瘤学的血红蛋白抑制剂， 并推进对小分子-大分子 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射线晶体学， 分子模拟技术来发现先导分子， 活性化合物在分子水平上的作用机制。 的 将合成相应的分子，并且溶液和细胞 将进行研究以评价体外活性和潜力 新分子的毒性问题。 我们已经从 从基础实验室研究到临床试验阶段， FDA. 我们的具体目标包括：前药类药物的合成和测试 防粘剂的类似物.其它芳族化合物的合成和试验 醛和衍生物的无毒原料或天然 作为潜在的抗氧化剂的产品.设计合成和检验 血红蛋白的新型别构调节剂;脱氧- 抗镰状细胞药物12 C79的孵育Hb结合位点（第一个 从血红蛋白的3D结构重新设计的治疗剂， 达到临床试验）和溶液结合测量; 测定了活性抗粘剂和四种抗粘剂的溶液结合常数， 血红蛋白变构效应物的分类. 抗氧化剂和氧解离的别构抑制剂 血红蛋白溶液曲线.溶液结合常数的比较 与变构抑制剂的P50值，以确定是否 可以用蛋白质系统观察到内在活性; 活性分子的结合位点和相互作用 晶体学上;评价阳性和 负极性和疏水相互作用使用新的计算机软件 （HINT）在前一个提案中开发;进一步开发 HINT软件;测量活性化合物对聚合物的流变学效应 红细胞;别构抑制剂和抗缺血剂的评价 在各种体外和体内系统中以及血液测量中 水平和%血红蛋白反应。

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.