Bissantz Caterina, Schalon Claire, Guba Wolfgang, Stahl Martin
Pharmaceuticals Division, Molecular Structure and Design, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Proteins. 2005 Dec 1;61(4):938-52. doi: 10.1002/prot.20651.
The aim of this study was to investigate the usefulness of structure-based virtual screening (VS) for focused library design in G protein-coupled receptors (GPCR) projects on the example of 5-HT(2c) agonists. We compared the performance of structure-based VS against two different homology models using FRED for docking and ScreenScore, FlexX, and PMF for rescoring with the results of 12 ligand-based similarity searches using four different query compounds and three different similarity metrics (Daylight, FTree, Phacir). The result of the similarity search showed much variation, from an enrichment factor up to 3.2 to worse than random, whereas the structure-based VS gave a more stable result with a constant enrichment factor around 2. Additionally, actives retrieved by the structure-based approach were more diverse than the actives among the top scorers of the similarity searches. Based on these results, we suggest basing a focused library design for a GPCR project on a combination of a ligand-based similarity search and structure-based docking.
本研究的目的是以5-HT(2c)激动剂为例，研究基于结构的虚拟筛选（VS）在G蛋白偶联受体（GPCR）项目中用于聚焦文库设计的效用。我们使用FRED进行对接，并用ScreenScore、FlexX和PMF进行重评分，将基于结构的VS与两种不同的同源模型的性能进行了比较，并将其结果与使用四种不同查询化合物和三种不同相似性度量（Daylight、FTree、Phacir）进行的12次基于配体的相似性搜索的结果进行了比较。相似性搜索的结果差异很大，富集因子高达3.2，也有比随机情况更差的，而基于结构的VS给出了更稳定的结果，富集因子恒定在2左右。此外，通过基于结构的方法检索到的活性物质比相似性搜索得分最高者中的活性物质更多样化。基于这些结果，我们建议在GPCR项目的聚焦文库设计中，将基于配体的相似性搜索和基于结构的对接相结合。
