DESIGN AND DEVELOPMENT OF POTENTIAL ANTISICKING AGENTS

我们的长期目标是开发安全、有效的药物， 治疗镰状细胞性贫血 我们的方法包括使用 通过X射线晶体学获得的结构信息， 合理的各种生化和生物测定结果 设计新化合物，选择现有药物， 选择/设计的分子的后续修饰， 提高其抗粘性能。 继续我们的镰状细胞 研究中，我们建议研究：1）二卤代丙烯酰苯氧基 酸和碱的结合使用X射线信息设计 在血红蛋白分子上的两个位点上的依他尼酸; 2） 氯喹和奎纳克林的类似物，现有的药物目前 用于已知被红细胞吸收的其他目的 体内; 3）取代的4-（2-硝基-1-丁烯基）-苯氧基酸和 碱; 4）各种4-（2-亚甲基烷基磺酰基）-苯氧基酸和 与镰状血红蛋白共价反应的碱基;和5） 有效的、非共价作用的 茴香酸系列 在大学的药物设计研究所 我们将继续测定X射线晶体 结构，运行抗胶凝试验，执行溶液结合 研究，执行能量计算，并模拟药物-蛋白质 交互. 我们也将继续与M。 Perutz和他在MRC分子生物学实验室的同事们 生物学（剑桥，英国）在结合位点的X射线测定 和分子建模。 发现化合物具有显著的 抗胶凝效果或其它所需性能将受到 一系列的测试 在药物设计研究所，我们将 测量它们在体外被红细胞摄取， 氧亲和力和红细胞变形性。 它们的变构效应 对聚合反应的影响将由C. Poyart at Punchem（巴黎）. E. 奥林杰在美国。位于查佩尔山的北卡罗来纳州将评估 它们对红细胞体积、红细胞内离子转运的影响 膜和细胞变形性。 O.卡斯特罗在霍华德大学。将 评估它们对红细胞存活时间的影响。 因此，有了这个 合作者网络和NHLBI支持，我们将继续 我们的最终目标是发展安全、有效、 抗癫痫药

Our long-term goal is to develop drugs for the safe, effective treatment of sickle cell anemia. Our approach involves the use of structural information obtained by X-ray crystallography and results of various biochemical and biological assays in the rational design of new compounds, selection of existing drugs, and subsequent modification of selected/designed molecules to enhance their antisickling properties. In continuing our sickle cell research, we propose to study: 1) dihalogenated acrylophenoxy acids and bases designed using X-ray information on the binding of ethacrynic acid at two sites on the hemoglobin molecule; 2) analogs of chloroquine and quinacrine, existing drugs currently used for other purposes that are known to be taken up by red cells in vivo; 3) substituted 4-(2-nitro-1-butenyl)-phenoxy acids and bases; 4) various 4-(2-methylenealkylsulfonyl)-phenoxy acids and bases that react covalently with sickle hemoglobin; and 5) covalently-acting derivatives of the potent, non-covalently-acting anisic acids series. At the Drug Design Institute at the University of Pittsburgh, we will continue to determine X-ray crystal structures, run antigelling assays, perform solution binding studies, perform energy calculations, and model drug-protein interactions. We also will continue our collaboration with M. Perutz and his colleagues at the MRC Laboratory of Molecular Biology (Cambridge, UK) in X-ray determination of binding sites and molecular modeling. Compounds found to have a significant antigelling effect or other desirable properties will be subjected to a series of tests. At the Drug Design Institute, we will measure their in vitro uptake by red cells and their effects on oxygen affinity and red cell deformability. Their allosteric effect on polymerization will be studied by C. Poyart at INSERM (Paris). E. Orringer at the U. of North Carolina at Chapel Hill will assess their effects on red cell volume, ion transport across the red cell membrane, and cell deformability. O. Castro at Howard U. will evaluate their effect on red cell survival time. Thus, with this network of collaborators and NHLBI support, we will continue to progress toward our ultimate goal of developing safe, effective antisickling drugs.