STUDIES IN NEW METHODS OF DRUG DESIGN

该提案概述了四个具体目标，直接侧重于 用于现代药物设计的基于结构的方法。 (1)在晶体中配体结合和占据的研究中， 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 在溶液中忠实地再现结合。(2)在蛋白质的研究中- 结合水，方法将开发预测网站的紧密结合 水和扩大结构的信息内容， 核磁共振光谱或X射线晶体学在中等分辨率。(3)在 谷胱甘肽还原酶（GR）和锥虫硫酮还原酶（TR）的研究， 几种新的GR和TR抑制剂，基于目前可用或 新开发的基于结构的设计方法，将 综合和评估。(4)在扩展表面结构的研究中， 已知酶配体将延伸到特异性置换结合的 水分子除了在GR和TR上测试这些想法外，新的溶菌酶 和HIV蛋白酶抑制剂将被合成，以研究是否 结合亲和力的基于熵的增量改进可以 办妥了一批

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.