COMPUTER-AIDED DRUG DESIGN/DISCOVERY FOR CHAGAS DISEASE

开发治疗克鲁兹毛滴虫的新药物的计划 介绍了引起查加斯病的寄生虫。克鲁赞，一个 半胱氨酸蛋白酶被确定为基于结构的药物的靶点 探索计划。克鲁扎因的三维结构模型 通过与其他已知结构的半胱氨酸蛋白酶同源而构建 最近确定的克鲁扎因的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，一个数据库 大约7万个可购买的小分子。本文件中选择的化合物 以计算机为基础的屏幕将以实验为特征。我们预计 2%-10%的计算机选择的抑制剂将是有效的 在浓度低于100微米的情况下对该酶进行实验。 我们已经鉴定出活性在2-4微米的克鲁萨因抑制剂。 浓度。自由能微扰计算将用于 帮助合成化学家开发更活跃的化合物。有些人会是 基于从计算机数据库中得到的非肽性导联 搜索，而其他的将是纳米分子机制的类似物 缓蚀剂Z-Phe-Arg-FMK(Z=羧基苯甲氧基，FMK=氟甲基酮) 已经被修改，以消除多肽字符。亲密的互动 在分子生物学、结构生物学、合成化学和 计算化学将被用于开发一种基于结构的药物 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.