Background: 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.

Objective: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

背景：3-磷酸肌醇依赖性蛋白激酶1（PDK1）最近被认为是有吸引力且即将到来的抗癌靶标。蛋白质数据库（PDB）共结晶的晶体不仅提供了严格的理论数据，而且还提供了可以探索并用于发现新命中的现实的分子识别数据。

目的：这促使我们通过Discovery Studio 4.5（DS 4.5）中基于结构的受体-配体药效团产生技术研究PDK1结合口袋内共结晶的配体接触。

方法：因此，收集和研究了35个PDK1晶体。验证每个单个配体相互作用，并将重要的配体转化为相应的药效学特征。产生的药效团通过受体工作特征（ROC）曲线分析进行评分。

结果：结果，产生并分类了169个药效基团，其中11个药效基团的ROC-AUC结果良好，选择性值大于8。药效基团1UU3_2_01由于其可接受的有效性标准和可接受性而特别用作筛选NCI数据库的搜索过滤器独特的正离子化功能。揭示了几种低微摩尔PDK1抑制剂。最有效的结果显示抗PDK1 IC50值为200 nM，对SW480细胞系的抑制率为70％。

结论：最终，将活性命中物停靠在PDK1结合口袋内，并分析了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。