STRUCTURAL BIOLOGY OF AIDS RELATED TARGETS AND LIGANDS

(改编自应用程序)：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 瞄准艾滋病治疗的新靶点。新的战略将是 用于获取关于信封的结构信息 糖蛋白(gp120/gp41)，尽管作出了相当大的努力，但尚未 屈服于详细的结构确定。为…制定战略 针对RNA元件，TAR和RRE的新结构将被用作 发现配基的基础。HIV衍生多肽的结构， 与II类MHC蛋白络合，将被测定并用于指导 人工合成T细胞抗原的设计。测定方法的研究 高分辨率的结构(X射线结晶学、核磁共振光谱学) 将在这些研究中使用。翻译这样一个词的主要障碍是 结构进入新的治疗方法是缺乏有效的，可重复的和 先导化合物设计的概括性方法。因此，a 拟议计划的主要目标是开发新的计算 基于结构的药物设计方法学。基于自由能的模型， 特别强调静电相互作用，将是 发展起来的。将采取两个步骤，以确保迅速和 为测试这些计算方法提供了大量的实验反馈。 首先，计算方法将应用于正在被 在该计划内进行了实验研究。第二，该计划将 利用成熟的组合合成方法来辅助 识别配基，使实验评估的 简化了计算方法。

(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.