Bicombinatorial discovery of small molecule tags

描述：(申请人提供)开发一种新的双组合 筛选将允许分离小分子化合物(约180道尔顿) 与单个细胞内的蛋白质发生特异性的相互作用。通过筛选 化合物组合文库与蛋白质组合文库 目标发现特定化合物-蛋白质对的机会将是 最大化。通常情况下，化合物必须与蛋白质在 具体来说，就是命令。这块屏幕将利用系链技术， 它在小分子和一个 半胱氨酸作用于蛋白质以稳定相互作用的复合体。这使得 即使当相互作用能很低时，特定的结合也是如此，所以 发现相互作用的分子显著增加，这种化合物 图书馆可以相对较小。这些化合物可以迅速转化为 研究蛋白质定位的荧光标记，或亲和化合物 分离出他们单独识别的蛋白质和复合体中的蛋白质。这些化合物将 也可作为药物发现的新型先导化合物。与之形成鲜明对比的是 专注于单一蛋白质靶点的传统药物筛选 双组合筛查应该同时显示哪种化学活动最多 有效地结合蛋白质，以及哪些化学成分赋予 反专一性。它也可能暗示一些未被开发的家庭 也适合作为药物靶标的蛋白质。

DESCRIPTION: (provided by applicant) Development of a novel bicombinatorial screen will allow isolation of small molecule compounds (about 180 daltons) that interact specifically with individual intracellular proteins. By screening a combinatorial library of compounds against a combinatorial library of protein targets the chance of discovering specific compound-protein pairs will be maximized. Typically a compound must interact with a protein very strongly in order to be specific. This screen will take advantage of tethering technology, which uses a secondary disulfide tether between the small molecule and a cysteine on the protein to stabilize interacting complexes. This allows specific binding even when the interaction energy is low, so the likelihood of finding interacting molecules is dramatically increased, and the compound library can be relatively small. The compounds can be rapidly converted to fluorescent tags to study protein localization, or to affinity compounds to isolate the protein they recognize alone and in complexes. These compounds will also be useful as novel lead compounds for drug discovery. In contrast to conventional drug screens which focus on a single protein target, the bicombinatorial screen should suggest both which chemical moities are the most effective in binding proteins, and which chemical constituents confer anti-specificity. It may also be able to suggest some unexploited families of proteins that would also be suitable as drug targets.