Grup d'Enginyeria Molecular, Institut Químic de Sarriá-IQS, Universitat Ramon Llull, Barcelona, Spain.
J Mol Graph Model. 2012 Sep;38:123-36. doi: 10.1016/j.jmgm.2012.06.010. Epub 2012 Jul 3.
Herein we analyze in depth the receptor-based virtual screening (VS) performance of the five recent crystallized CXCR4 structures along with a CXCR4 rhodopsin-based homology model. All CXCR4 Protein Data Bank (PDB) structures are co-crystallized with a small organic antagonist except structure 3OE0, which is co-crystallized with a cyclic peptide analog. Evaluation of the CXCR4 models was done by retrospective docking-based VS using a test set of 248 known CXCR4 inhibitors from 4 different chemotype families and 4696 different presumed inactives. The performance of the docking protocol using the five different protein structures was assessed in terms of pose prediction and hits detection using 12 different docking scoring functions and a scoring function with rescoring. Results show that 3OE6 structure achieves the highest docking-based performance with an average area under the curve (aAUC) of 0.84 and an average enrichment factor (aEF) of 11.7 at 1% of decoys screened. CXCR4 rhodopsin-like homology model performs comparable to the crystallized structures in the 1% of database screened. Moreover, a detailed analysis of the retrospective docking results using the CXCR4 homology model in Discovery Studio allows us to hypothesize the existence of multiple binding sub-sites in CXCR4 binding pocket.
在此，我们深入分析了最近五个结晶化的 CXCR4 结构以及基于 CXCR4 视紫红质的同源模型的基于受体的虚拟筛选（VS）性能。除了与环状肽类似物共结晶的结构 3OE0 外，所有 CXCR4 蛋白质数据库（PDB）结构都与小分子拮抗剂共结晶。使用来自 4 个不同化学型家族的 248 种已知 CXCR4 抑制剂和 4696 种假定非活性物质的测试集，通过基于回溯的对接 VS 评估 CXCR4 模型。使用 12 种不同的对接打分函数和一种带有重打分的打分函数，根据构象预测和命中检测来评估使用五种不同蛋白质结构的对接方案的性能。结果表明，3OE6 结构具有最高的对接性能，平均曲线下面积（aAUC）为 0.84，平均富集因子（aEF）为 11.7，在筛选的 1%的诱饵中。在筛选的 1%的数据库中，CXCR4 类视紫红质同源模型的性能与结晶结构相当。此外，使用 Discovery Studio 中基于 CXCR4 同源模型的回溯对接结果的详细分析使我们能够假设 CXCR4 结合口袋中存在多个结合亚位点。
