Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad 382 481, Gujarat, India.
J Mol Graph Model. 2013 May;42:17-25. doi: 10.1016/j.jmgm.2013.01.010. Epub 2013 Feb 24.
Protein kinase B (PKB) is a key mediator of proliferation and survival pathways that are critical for cancer growth. Therefore, inhibitors of PKB are useful agents for the treatment of cancer. Herein, we describe pharmacophore-based virtual screening combined with docking study as a rational strategy for identification of novel hits or leads. Pharmacophore models of PKB β inhibitors were established using the DISCOtech and refined with GASP from compounds with IC50 values ranging from 2.2 to 246nM. The best pharmacophore model consists of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) site and two hydrophobic (HY) features. The pharmacophore models were validated through receiver operating characteristic (ROC) and Güner-Henry (GH) scoring methods indicated that the model-3 was statistically valuable and reliable in identifying PKB β inhibitors. Pharmacophore model as a 3D search query was searched against NCI database. Several compounds with different structures (scaffolds) were retrieved as hits. Molecules with a Qfit value of more than 95 and three other known inhibitors were docked in the active site of PKB to further explore the binding mode of these compounds. Finally in silico pharmacokinetic and toxicities were predicted for active hit molecules. The hits reported here showed good potential to be PKB β inhibitors.
蛋白激酶 B（PKB）是增殖和存活途径的关键介质，这些途径对癌症的生长至关重要。因此，PKB 的抑制剂是治疗癌症的有用药物。在此，我们描述了基于药效团的虚拟筛选与对接研究相结合，作为鉴定新型命中或先导物的合理策略。使用 DISCOtech 建立了 PKBβ抑制剂的药效团模型，并使用 GASP 对 IC50 值范围为 2.2 至 246 nM 的化合物进行了细化。最佳药效团模型由一个氢键受体（HBA）、一个氢键供体（HBD）位点和两个疏水性（HY）特征组成。通过接受者操作特性（ROC）和 Güner-Henry（GH）评分方法验证了药效团模型，表明模型-3在识别 PKBβ抑制剂方面具有统计学价值和可靠性。将药效团模型作为 3D 搜索查询在 NCI 数据库中进行搜索。检索到了具有不同结构（支架）的几种化合物作为命中。具有 Qfit 值大于 95 的分子和另外三个已知抑制剂被对接在 PKB 的活性位点，以进一步探索这些化合物的结合模式。最后，对活性命中分子进行了虚拟药代动力学和毒性预测。报告的这些命中化合物显示出成为 PKBβ抑制剂的良好潜力。
