Liu Qian, Masek Brian, Smith Karl, Smith Julian
Tripos, Inc., 1699 South Hanley Road, St. Louis, Missouri 63144, USA.
J Med Chem. 2007 Nov 1;50(22):5392-402. doi: 10.1021/jm070750k. Epub 2007 Oct 6.
Here we describe a computer-assisted de novo drug design method, EAISFD, which combines the de novo design engine EA-Inventor with a scoring function featuring the molecular docking program Surflex-Dock. This method employs tagged fragments, which are preserved substructures in EA-Inventor used for base fragment matching in Surflex-Dock, for constructing ligand structures under specific binding motifs. In addition, a target score mechanism is adopted that allows EAISFD to deliver a diverse set of desired structures. This method can be used to design novel ligand scaffolds (lead generation) or to optimize attachments on a fixed scaffold (lead optimization). EAISFD has successfully suggested many known inhibitor scaffolds as well as a number of new scaffold types when applied to p38 MAP kinase.
在此，我们描述了一种计算机辅助的从头药物设计方法——EAISFD，它将从头设计引擎EA-Inventor与具有分子对接程序Surflex-Dock的评分函数相结合。该方法采用标记片段，这些片段是EA-Inventor中用于Surflex-Dock碱基片段匹配的保留子结构，用于在特定结合基序下构建配体结构。此外，还采用了目标评分机制，使EAISFD能够提供多种所需结构。该方法可用于设计新型配体支架（先导化合物生成）或优化固定支架上的连接（先导化合物优化）。当应用于p38丝裂原活化蛋白激酶时，EAISFD成功地提出了许多已知的抑制剂支架以及一些新的支架类型。
