On the Value of Homology Models for Virtual Screening: Discovering hCXCR3 Antagonists by Pharmacophore-Based and Structure-Based Approaches
On the Value of Homology Models for Virtual Screening: Discovering hCXCR3 Antagonists by Pharmacophore-Based and Structure-Based Approaches
复制标题
论同源模型对虚拟筛选的价值：通过基于药效团和结构的方法发现 hCXCR3 拮抗剂
DOI：
10.1021/ci300067q
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发表时间：
2012-05-01
影响因子：
5.6
通讯作者：
Xu, Jun
中科院分区：
文献类型：
--
作者：
Huang, Dane;Gu, Qiong;Xu, Jun
人趋化因子受体CXCR 3（hCXCR 3）拮抗剂作为抗病毒、抗肿瘤和抗炎剂具有潜在的治疗应用。提出了一种基于药效团和结构的虚拟筛选方法。建立了三维QSAR药效团模型和基于结构的对接模型，用于hCXCR 3拮抗剂的虚拟筛选。通过同源模建和分子动力学（MD）模拟构建hCXCR 3拮抗剂结合位点。通过结合基于结构和基于配体的筛选结果，95%的化合物满足药效团或对接评分标准，如果采用两种搜索的联合，则将被选为命中物。药效团模型的假阴性率为15%，同源性模型为14%，组合模型为5%。因此，药效团模型和结构结合模型的一致性为219/273 = 80%。虚拟筛查方案的命中率为273/286 = 95%。本工作表明药效团模型和同源性模型的质量可以通过两个模型的一致性来衡量，并且通过结合两种虚拟筛选方法可以减少虚拟筛选中的假阴性。
Human chemokine receptor CXCR3 (hCXCR3) antagonists have potential therapeutic applications as antivirus, antitumor, and anti-inflammatory agents. A novel virtual screening protocol, which combines pharmacophore-based and structure-based approaches, was proposed. A three-dimensional QSAR pharmacophore model and a structure-based docking model were built to virtually screen for hCXCR3 antagonists. The hCXCR3 antagonist binding site was constructed by homology modeling and molecular dynamics (MD) simulation. By combining the structure-based and ligand-based screenings results, 95% of the compounds satisfied either pharmacophore or docking score criteria and would be chosen as hits if the union of the two searches was taken. The false negative rates were 15% for the pharmacophore model, 14% for the homology model, and 5% for the combined model. Therefore, the consistency of the pharmacophore model and the structural binding model is 219/273 = 80%. The hit rate for the virtual screening protocol is 273/286 = 95%. This work demonstrated that the quality of both the pharmacophore model and homology model can be measured by the consistency of the two models, and the false negatives in virtual screening can be reduced by combining two virtual screening approaches.