COMPUTER-AIDED DRUG DESIGN/DISCOVERY FOR CHAGAS DISEASE

一个开发治疗T.克鲁齐 寄生虫负责恰加斯病，提出。 Cruzain，a 半胱氨酸蛋白酶被鉴定为基于结构的药物的靶点 探索计划 Cruzain的三维结构模型 通过与已知结构的其它半胱氨酸蛋白酶的同源性构建， 最近确定的cruzain的x射线结构将被用作模板 对于精细化学品目录的计算机筛选， 大约7万种可购买的小分子。 本发明中选择的化合物 基于计算机的屏幕将通过实验来表征。 我们预计 2-10%的计算机选择的抑制剂将被激活 在实验中，该酶的浓度小于100 μ M。 我们已经鉴定出cruzain抑制剂在2-4 μ M时有活性， 浓度的 自由能微扰计算将用于 帮助合成化学家开发更有活性的化合物。 有的会 基于从计算机数据库中导出的非肽线索 搜索，而其他将是纳摩尔机制的类似物 抑制剂Z-Phe-Arg-FMK（Z=苄氧羰基，FMK =氟甲基酮）， 已经被改变以消除肽特征。 密切互动 分子生物学、结构生物学、合成化学和 计算化学将用于开发基于结构的药物 设计周期

A program for the development of new agents to treat T. Cruzi, the parasite responsible for Chagas' Disease, is presented. Cruzain, a cysteine protease is identified as a target for a structure based drug discovery program. Models of the three-dimensional structure of cruzain built by homology to other cysteine proteases of known structure and the recently determined x-ray structure of cruzain will be used as a template for the in compuo screening of the fine chemicals directory, a data base of about 70,000 purchaseable small molecules. Compounds selected in this computer based screen will be characterized experimentally. We expect that 2-10% of the computer selected inhibitors will be active experimentally against the enzyme at concentrations less than 100 microM. Already, we have identified cruzain inhibitors active at 2-4 microM concentrations. Free energy perturbation calculations will be used to help the synthetic chemists develop more active compounds. Some will be based on the non-peptidic leads derived from the computer data base searches, while others will be analogs of the nanomolar mechanistic inhibitor Z-Phe-Arg-FMK (Z= carbobenzoxy, FMK = fluoromethyl ketone) that have been altered to eliminate peptide character. A close interaction between molecular biology, structural biology, synthetic chemistry and computational chemistry will be used to exploit a structure based drug design cycle.