THREE DIMENSIONAL HIV RNA GENOME TARGETED DRUG LEADS

该项目的总体目标是利用一种新的药物设计范式开发有前途的候选药物，该设计范式基于最初的三维RNA结构计算筛选约255,000种商业可用化合物，利用HIV-1基因组部分的三维结构与选定的RNA靶标结合。具体地说，反式激活反应元件(TAR)和二聚体连接位点(DLS)被提出作为靶点。后者是药物设计的新靶点。良好的计算“命中率”将在功能分析中进行抑制测试。其中最好的将被用于核磁共振研究，以验证与RNA靶标的结合模式。最好的候选化合物是分子量通常小于500道尔顿的水溶性、非肽、非核苷酸有机化合物，但可能有必要考虑稍微大一些的化合物作为先导化合物。对潜在先导及其RNA靶标形成的络合物的核磁共振结构研究应能深入了解支配亲和力和特异性的特征。将通过计算和实验组合化学来选择有希望的线索进行进一步的开发。并对该方法的进一步发展进行了展望。

The overall goal of this project is to develop promising drug candidate leads using a new drug design paradigm based on initial three-dimensional RNA-structure-based computational screening of about 255,000 commercially available compounds for binding to selected RNA targets using the three-dimensional structure of portions of the HIV-1 genome. Specifically, the transactivation response element (TAR) and the dimer linkage site (DLS) are proposed as targets. The latter is a novel target for drug design. Good computational "hits" will be tested for inhibition in functional assays. The best of these will be utilized in NMR studies to verify the mode of binding to the RNA target. The best candidates will be water-soluble, nonpeptide, nonnucleotide organic compounds generally with molecular weight less than 500 daltons, but it may be necessary to consider slightly larger compounds as leads. The NMR structural studies of complexes formed with potential leads and their RNA targets should yield insight into features governing affinity and specificity. Promising leads will be selected for further development via computational and experimental combinatorial chemistry. Some further development of the methodology is proposed.