Faculty of Pharmaceutical Sciences, The Hashemite University, P.O. Box 330127 Zarqa, 13133 Jordan
Faculty of Pharmacy, Zarqa University, Zarqa, 13132, Jordan
Med Chem. 2020;16(7):860-880. doi: 10.2174/1573406415666190724131048.
3-Phosphoinositide Dependent Protein Kinase-1 (PDK1) is being lately considered as an attractive and forthcoming anticancer target. A Protein Data Bank (PDB) cocrystallized crystal provides not only rigid theoretical data but also a realistic molecular recognition data that can be explored and used to discover new hits.
This incited us to investigate the co-crystallized ligands' contacts inside the PDK1 binding pocket via a structure-based receptor-ligand pharmacophore generation technique in Discovery Studio 4.5 (DS 4.5).
Accordingly, 35 crystals for PDK1 were collected and studied. Every single receptorligand interaction was validated and the significant ones were converted into their corresponding pharmacophoric features. The generated pharmacophores were scored by the Receiver Operating Characteristic (ROC) curve analysis.
Consequently, 169 pharmacophores were generated and sorted, 11 pharmacophores acquired good ROC-AUC results of 0.8 and a selectivity value above 8. Pharmacophore 1UU3_2_01 was used in particular as a searching filter to screen NCI database because of its acceptable validity criteria and its distinctive positive ionizable feature. Several low micromolar PDK1 inhibitors were revealed. The most potent hit illustrated anti-PDK1 IC50 values of 200 nM with 70% inhibition against SW480 cell lines.
Eventually, the active hits were docked inside the PDK1 binding pocket and the recognition points between the active hits and the receptor were analyzed that led to the discovery of new scaffolds as potential PDK1 inhibitors.
3-磷酸肌醇依赖的蛋白激酶-1（PDK1）最近被认为是一个有吸引力和有前途的抗癌靶点。蛋白质数据库（PDB）共结晶晶体不仅提供了刚性的理论数据，还提供了现实的分子识别数据，可以用来发现新的命中。
这促使我们通过结构基于受体-配体药效团生成技术在 Discovery Studio 4.5（DS 4.5）中研究 PDK1 结合口袋内共结晶配体的接触。
因此，收集并研究了 35 个 PDK1 晶体。每个受体-配体相互作用都经过验证，并将显著的相互作用转化为相应的药效团特征。生成的药效团通过接收者操作特征（ROC）曲线分析进行评分。
总共生成并排序了 169 个药效团，其中 11 个药效团获得了良好的 ROC-AUC 结果为 0.8，选择性值高于 8。药效团 1UU3_2_01 因其可接受的有效性标准和独特的正可离子化特征而被特别用作搜索过滤器来筛选 NCI 数据库。揭示了几种低微摩尔 PDK1 抑制剂。最有效的命中物显示出对 PDK1 的 IC50 值为 200 nM，对 SW480 细胞系的抑制率为 70%。
最终，将活性命中物对接进 PDK1 结合口袋内，并分析活性命中物与受体之间的识别点，从而发现了新的支架作为潜在的 PDK1 抑制剂。
