STRUCTURAL BIOLOGY OF AIDS RELATED TARGETS AND LIGANDS

（改编自应用）：本研究计划的最终目标是 开发基于结构的药物设计方法，重点是 为治疗艾滋病寻找新的目标。新战略将是 获取信封的结构信息 糖蛋白（gp 120/gp 41），尽管付出了相当大的努力， 产生详细的结构测定。制定战略， 靶向RNA元件，TAR和RRE的新结构将被用作 是发现配体的基础HIV衍生肽的结构， 与II类MHC蛋白复合，将被确定并用于指导 设计合成T细胞抗原测定方法 高分辨率结构（X射线晶体学、NMR光谱学） 将用于这些研究。在翻译这样的一个主要障碍 新疗法的结构是缺乏有效的，可重复的， 为先导化合物的设计提供了可推广的方法。 因此 该计划的主要目的是开发新的计算 基于结构的药物设计方法。自由能源模型， 特别强调静电相互作用，将 开发将采取两个步骤，以确保有迅速和 大量的实验反馈用于测试这些计算方法。 首先，计算方法将应用于正在被 在程序中进行实验研究。其次，该计划将 利用成熟的组合合成方法， 识别配体，以便实验评价 方便了计算方法。

(Adapted from application): The ultimate goal of this research program is to develop methods for structure-based drug design, with an emphasis on aiming at new targets for the treatment of AIDS. New strategies will be taken toward obtaining structural information about the envelope glycoprotein (gp120/gp41), which, despite considerable efforts, has yet to yield to detailed structural determination. To develop strategies for targeting RNA elements, the new structures of TAR and RRE will be used as the basis for ligand discovery. The structures of HIV-derived peptides, complexed with class II MHC proteins, will be determined and used to guide the design of synthetic T-cell antigens. Methods for determining structures at high resolution (X-ray crystallography, NMR spectroscopy) will be used in these studies. A major hurdle in the translation of such structure into new therapies is the lack of effective, reproducible and generalizable approaches for the design of lead compounds. Therefore, a key aim of the proposed program is to develop new computational methodologies for structure-based drug design. Free-energy based models, with a particular emphasis on electrostatic interactions, will be developed. Two steps will be taken to ensure that there is rapid and plentiful experimental feedback for testing these computational methods. First, the computational methods will be applied to targets that are being investigated experimentally within the program. Second, the program will utilize well-established combinatorial synthesis methods to assist identification of ligands, so that experimental evaluation of the computational methods is facilitated.