Combinatorial and computational approaches in structure-based drug design.
Combinatorial and computational approaches in structure-based drug design.
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发表时间：
1998-07
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通讯作者：
Hugo Kubinyi
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作者：
Hugo Kubinyi
越来越多的蛋白质三维结构和基于结构的方法的成功，导致了一些实验和理论技术的发展，蛋白质配体的合理设计。组合化学显著加快了潜在新药候选物的合成。多样性的考虑，以及生物靶标的3D结构信息的使用，将巨大文库的大小减小到合理设计的配体的合理数量。新的核磁共振技术（核磁共振合成孔径雷达）允许从低得多的亲和力的小分子的高亲和力配体的建设。计算机辅助药物设计使用构建、连接和/或刚性对接程序来搜索某个结合位点的配体。评分函数根据其估计的结合亲和力提供设计的配体的等级顺序。计算机辅助药物设计的进一步发展是用于分子的灵活排列、配体与其结合位点的灵活对接以及从片段的组合文库合成容易获得的配体的逐步组装的自动化方法。
The increasing number of protein 3D structures and the success of structure-based approaches has led to the development of several experimental and theoretical techniques for the rational design of protein ligands. Combinatorial chemistry significantly speeds up the synthesis of potential new drug candidates. Diversity considerations, as well as the use of 3D structural information of the biological targets, reduce the size of huge libraries to a reasonable number of rationally-designed ligands. New NMR techniques (SAR by NMR) allow the construction of high-affinity ligands from small molecules with much lower affinities. Computer-aided drug design uses building, linking, and/or rigid docking procedures to search for ligands for a certain binding site. Scoring functions provide a rank order of the designed ligands according to their estimated binding affinities. Further developments in computer-aided drug design are automated approaches for the flexible alignment of molecules, the flexible docking of ligands to their binding sites, and the stepwise assembly of synthetically easily accessible ligands from combinatorial libraries of fragments.