STUDIES IN NEW METHODS OF DRUG DESIGN

该提案概述了四个具体目标，这些目标直接侧重于 现代药物设计中基于结构的方法使用的方法学。 (1)在研究配体在晶体中的结合和占据时，方法将 用于估计结合在蛋白质中的配体的占有率 晶体，用于确定固态配体结合是否 在溶液中忠实地复制结合。(2)在蛋白质的研究中- 结合水，将开发方法来预测紧密结合的位置 并扩展由下列因素确定的结构的信息内容 中分辨率的核磁共振光谱学或X射线结晶学。(3)在 谷胱甘肽还原酶(GR)和锥硫酮还原酶(TR)的研究 几种新的GR和TR抑制剂，基于目前可用的或 新开发的基于结构的设计方法，将是 综合评价。(4)在扩展表面结构的研究中 已知的酶配体将被扩展到特定的置换结合 水分子。除了在GR和TR上测试这些想法外，新的溶菌酶 并将合成HIV蛋白酶抑制剂，以调查是否 绑定亲和性中基于熵的增量改进可以是 已实现。

This proposal outlines four specific aims which focus directly on methodology for use in structure-based approaches to modern drug design. (1) In studies on ligand binding and occupancy in crystals, methods will be developed for estimating the occupancy of a ligand bound in a protein crystal, ad for ascertaining whether solid state ligand binding faithfully reproduces binding in solution. (2) In studies on protein- bound water, methods will be developed to predict sites of tightly-bound water and to extend the information content of structures determined by NMR spectroscopy or x-ray crystallography at medium resolution. (3) In studies on glutathione reductase (GR) and trypanothione reductase (TR), several new inhibitors of GR and TR, based on currently available or newly developed structure-based design methodologies, will be synthesized and evaluated. (4) In studies on extended surface structures known enzyme ligands will be extended to specifically displace bound water molecules. Besides testing these ideas on GR and TR, new lysozyme and HIV protease inhibitors will be synthesized to investigate whether entropy-based incremental improvements in binding affinity can be achieved.