STRUCTURE/FUNCTION RELATIONSHIPS IN TREATMENT OF CANCER AND AIDS

统计力学算法(HAL、HALP、HALCO)被设计用于 评估两亲性螺旋结构和更一般的结构- 蛋白质和多肽中的功能关系。这些计算量 正在使用各种方法来定义结构和可能的问题 对人类白细胞抗原和包膜蛋白的免疫原性 艾滋病病毒。 还开发了一种新的蛋白质二级联合预测方法。 结构。该方法结合了神经网络、信息论、序列 同源性、疏水性、环势和两亲性标准 (包括HAL)。我们已经将其应用于对人类的结构化预测 和牛叶酸结合蛋白，这在细胞中是重要的 处理叶酸和抗肿瘤药物，如甲氨蝶呤。 定量结构/活性关系(QSAR)研究正在进行中 一组20种核苷转运到细胞内的抑制剂。同时， 一项分子力学研究正在对这种不寻常的类似物进行 核苷转运抑制剂双嘧达莫。我们小组发现， 双嘧达莫(和至少一种其他核苷转运抑制剂) 增强叠氮胸苷抗HIV-1复制的活性 培养的单核/巨噬细胞和T淋巴细胞(见报告#Z01CB 08392-02年度)。动物研究正在进行中，临床试验正在进行中 正在计划中，同时继续尝试了解 作用机制和分子结构/功能关系。

Statistical mechanical algorithms (HAL, HALP, HALCO) were devised for evaluating amphipathic helical structures and more general structure- function relationships in proteins and peptides. These computational approaches are being used to define issues of structure and possible immunogenicity with respect to HLA antigens and to the envelope polyprotein of HIV. Also developed was a new joint prediction approach to protein secondary structure. The method combines neural network, information theory, sequence homology, hydrophobicity, loop potential, and amphipathicity criteria (including HAL). We have applied it to structure predictions on the human and bovine folate binding proteins, which are important in the cellular handling of folates and antitumor drugs such as methotrexate. Quantitative structure/activity relationship (QSAR) studies are being done on a set of 20 inhibitors of nucleoside transport into cells. In parallel, a molecular mechanics study is being done on analogues of the unusual nucleoside transport inhibitor dipyridamole. Our group has found that dipyridamole (and at least one other nucleoside transport inhibitor) potentiates the activity of azidothymidine against HIV-1 replication in cultured monocyte/macrophages and T-lymphocytes (see report # Z01 CB 08392-02 LMMB) . Animal studies are in progress and clinical trials are being planned, in parallel with continuing attempts to understand the mechanisms of action and molecular structure/function relationships.