STRUCTURE-BASED DISCOVERY OF INHIBITORS OF THYMIDYLATE SYNTHASE
STRUCTURE-BASED DISCOVERY OF INHIBITORS OF THYMIDYLATE SYNTHASE
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DOI：
10.1126/science.8451640
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发表时间：
1993-03-05
期刊：
影响因子：
56.9
通讯作者：
PERRY, KM
中科院分区：
文献类型：
--
作者：
SHOICHET, BK;STROUD, RM;PERRY, KM
使用一种分子对接计算机程序（DOCK）对精细化学品目录（一个可商购化合物的数据库）进行筛选，以寻找与胸苷酸合成酶（TS，一种化疗靶点）互补的分子。除了检索到底物和几种已知的抑制剂外，DOCK还提出了一些此前未知的可能与该酶结合的抑制剂。其中三种化合物在亚毫摩尔浓度下抑制干酪乳杆菌TS。其中一种抑制剂，磺异苯酮，与TS以两种不同于DOCK所倾向的几何构型结晶：一个抗衡离子结合在底物位点，导致抑制剂位移6到9埃。复合物的结构表明活性位点中另一个可利用的结合区域。用与磺异苯酮空间相似的分子对该区域进行探测，从而鉴定出一系列在1到30微摩尔范围内抑制TS的酚酞类似物。这些抑制剂与酶的底物并不相似。酚酞与TS的晶体结构表明，它以一种类似于DOCK所提示的构型结合在靶点部位。
A molecular docking computer program (DOCK) was used to screen the Fine Chemical Directory, a database of commercially available compounds, for molecules that are complementary to thymidylate synthase (TS), a chemotherapeutic target. Besides retrieving the substrate and several known inhibitors, DOCK proposed putative inhibitors previously unknown to bind to the enzyme. Three of these compounds inhibited Lactobacillus casei TS at submillimolar concentrations. One of these inhibitors, sulisobenzone, crystallized with TS in two configurations that differed from the DOCK-favored geometry: a counterion was bound in the substrate site, which resulted in a 6 to 9 angstrom displacement of the inhibitor. The structure of the complexes suggested another binding region in the active site that could be exploited. This region was probed with molecules sterically similar to sulisobenzone, which led to the identification of a family of phenolphthalein analogs that inhibit TS in the 1 to 30 micromolar range. These inhibitors do not resemble the substrates of the enzyme. A crystal structure of phenolphthalein with TS shows that it binds in the target site in a configuration that resembles the one suggested by DOCK.