NEW STRATEGIES FOR DRUG DISCOVERY AND DEVELOPMENT

这个研究小组的中心目标是(1)开发新的分析和 癌症和艾滋病药物发现的实验战略，以及(2) 将这些策略应用于具有生物和治疗重要性的 有问题。 分析结果： L。神经网络在预测药物作用机理的基础上 在DTP的60细胞系抗癌药物筛选中的活性模式。 2.程序包(发现)，它集成了关于 化合物的化学结构、活性和分子靶标 美国国家情报局。顾名思义，发现是为了寻找小说而设计的。 迄今测试的48,000种化合物中的作用机制。 3.通过以下方式鉴定用于在筛选中替换的候选细胞系 乳腺、前列腺、靶向选择和靶向转染系。 4.临床预测的初步神经网络和统计方法 第二阶段的活动--基于活动模式的可评价药物 在屏幕上。 5.使用发现来识别我们所称的“p53逆转剂”，即， 在p53突变型细胞中比在p53野生型细胞中活性更高的化合物 台词。 6.在NCI的DIS数据库中进行QSAR研究和药效团搜索，以 寻找新的HIV-L整合酶抑制剂。 7.使用“信息密集型”战略创造信息 癌症和艾滋病药物发现计划之间的接口。 在实验研究方面，我们有： 1.鉴定NCI癌和NCI细胞中的mRNA和蛋白质靶点 艾滋病筛查。其中一个主要方面是二维凝胶电泳，以开发一种 关于细胞中数百种蛋白质的大规模资源数据库。 2.建立了鉴定二维蛋白质的质谱学方法 凝胶。 3.完成了实体瘤和血管内皮细胞中空纤维模型的建立 血管生成模型，两者都用于新疗法的体外测试。

This research group's central aims are (1) to develop new analytical and experimental strategies for drug discovery in cancer and AIDS, and (2) to apply those strategies to biologically and therapeutically important problems. Analytical results: l. Neural networks able to predict mechanism of drug action on the basis of patterns of activity in DTP's 60-cell line cancer drug screen. 2. A program package (DISCOVERY) that integrates information on the chemical structure, activity, and molecular targets of compounds tested by NCI. As the name suggests, DISCOVERY was designed to search for novel mechanisms of action among the 48,000 compounds tested to date. 3. Identification of candidate cell lines for replacement in the screen by breast, prostate, target-selected, and target-transfected lines. 4. Preliminary neural nets and statistical methods to predict clinical activity of phase II-evaluable drugs on the basis of patterns of activity in the screen. 5. Use of DISCOVERY to identify what we term "p53-inverse" agents, i.e., compound that appear more active in p53-mutant than in p53-wild type cell lines. 6. QSAR studies and pharmacophore searches in the NCI's DIS database to identify new inhibitors of HIV- l integrase. 7. Use of "information intensive" strategies to create an information interface between the cancer and AIDS drug discovery programs. With respect to experimental studies we are: 1. Characterizing mRNA and protein "targets" in cell of the NCI cancer and AIDS screens. A major aspect is 2-D gel electrophoresis to develop a large-scale resource database on hundreds of proteins in the cells. 2. Developing a mass spectrometry method to identify proteins in the 2-D gels. 3. Completing development of a hollow fiber model of solid tumors and an angiogenesis model, both for use in in vitro testing of new therapies.