Fechner Uli, Schneider Gisbert
Johann Wolfgang Goethe-Universität, Institut für Organische Chemie und Chemische Biologie, Marie-Curie-Str. 11, D-60439 Frankfurt, Germany.
J Chem Inf Model. 2006 Mar-Apr;46(2):699-707. doi: 10.1021/ci0503560.
It is demonstrated that the fragmentation of druglike molecules by applying simplistic pseudo-retrosynthesis results in a stock of chemically meaningful building blocks for de novo molecule generation. A stochastic search algorithm in conjunction with ligand-based similarity scoring (Flux: fragment-based ligand builder reaxions) facilitated the generation of new molecules using a single known reference compound as a template. This molecule assembly method is applicable in the absence of receptor-structure information. In a case study, we used imantinib (Gleevec) and a Factor Xa inhibitor as the reference structures. The algorithm succeeded in redesigning the templates from scratch and suggested several alternative molecular structures. The resulting designed molecules were chemically reasonable and contained essential substructure motifs. A comparison of molecular descriptors suggests that holographic descriptors might be advantageous over binary fingerprints for ligand-based de novo design.
结果表明，通过应用简单的伪逆合成法对类药物分子进行碎片化处理，可得到一批具有化学意义的用于从头生成分子的构建模块。一种随机搜索算法结合基于配体的相似性评分（Flux：基于片段的配体构建反应），以单一已知参考化合物为模板促进了新分子的生成。这种分子组装方法在缺乏受体结构信息的情况下也适用。在一个案例研究中，我们使用伊马替尼（格列卫）和一种凝血因子Xa抑制剂作为参考结构。该算法成功地从头重新设计了模板，并提出了几种替代分子结构。所得的设计分子在化学上是合理的，并且包含基本的子结构基序。分子描述符的比较表明，对于基于配体的从头设计，全息描述符可能比二元指纹更具优势。
