Center for Bioinformatics, University of Hamburg, Bundesstr. 43, 20146 Hamburg, Germany.
J Comput Aided Mol Des. 2011 Oct;25(10):931-45. doi: 10.1007/s10822-011-9473-6. Epub 2011 Sep 16.
De novo ligand design supports the search for novel molecular scaffolds in medicinal chemistry projects. This search can either be based on structural information of the targeted active site (structure-based approach) or on similarity to known binders (ligand-based approach). In the absence of structural information on the target, pharmacophores provide a way to find topologically novel scaffolds. Fragment spaces have proven to be a valuable source for molecular structures in de novo design that are both diverse and synthetically accessible. They also offer a simple way to formulate custom chemical spaces. We have implemented a new method which stochastically constructs new molecules from fragment spaces under consideration of a three dimensional pharmacophore. The program has been tested on several published pharmacophores and is shown to be able to reproduce scaffold hops from the literature, which resulted in new chemical entities.
从头设计配体支持在药物化学项目中寻找新的分子骨架。这种搜索可以基于靶标活性位点的结构信息（基于结构的方法），也可以基于与已知配体的相似性（基于配体的方法）。在缺乏靶标结构信息的情况下，药效团为寻找拓扑新颖的骨架提供了一种方法。片段空间已被证明是从头设计中具有多样性和可合成性的分子结构的有价值的来源。它们还提供了一种简单的方法来制定自定义化学空间。我们已经实现了一种新方法，该方法在考虑三维药效团的情况下从考虑的片段空间中随机构建新分子。该程序已经在几个已发表的药效团上进行了测试，并且能够重现文献中的骨架跃迁，从而产生新的化学实体。
