Bicombinatorial discovery of small molecule tags

描述：（由申请人提供）开发一种新型双组合 筛选将允许分离小分子化合物（约180道尔顿） 与单个细胞内蛋白质特异性相互作用。通过筛选 一个化合物的组合库和一个蛋白质的组合库 目标是发现特定化合物-蛋白质对的机会将是 最大化。通常，化合物必须与蛋白质非常强烈地相互作用， 为了具体。这个屏幕将利用网络共享技术， 它在小分子和 蛋白质上的半胱氨酸以稳定相互作用的复合物。这允许 特异性结合，即使当相互作用能低时， 发现相互作用的分子是显着增加，该化合物 图书馆可以相对较小。这些化合物可以迅速转化为 荧光标记来研究蛋白质定位，或亲和化合物， 分离出它们单独识别的蛋白质和复合物。这些化合物将 也可用作药物发现的新型先导化合物。相比 传统的药物筛选集中在单一的蛋白质靶点上， 双组合筛选应同时表明哪些化学部分是最重要的， 有效地结合蛋白质，以及哪些化学成分赋予 反特异性它也可能表明一些未被开发的家庭， 这些蛋白质也适合作为药物靶点。

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.