Cryptic pockets, which are not apparent in crystallographic structures, provide promising alternatives to traditional binding sites for drug development. However, identifying cryptic pockets is extremely challenging and the therapeutic potential of cryptic pockets remains unclear. Here, we reported the discovery of novel inhibitors for striatal-enriched protein tyrosine phosphatase (STEP), a potential drug target for multiple neuropsychiatric disorders, based on cryptic pocket detection. By combining the use of molecular dynamics simulations and fragment-centric topographical mapping, we identified transiently open cryptic pockets and identified 12 new STEP inhibition scaffolds through structure-based virtual screening. Site-directed mutagenesis verified the binding of ST3 with the predicted cryptic pockets. Moreover, the most potent and selective inhibitors could modulate the phosphorylation of both ERK1/2 and Pyk2 in PC12 cells.

中文翻译：

---

通过靶向计算揭示的神秘口袋来抑制富含纹状体的蛋白酪氨酸磷酸酶。

隐性口袋在晶体结构中并不明显，为药物开发提供了传统结合位点的有希望的替代方案。然而，识别隐袋极具挑战性，并且隐袋的治疗潜力仍不清楚。在这里，我们报告了基于神秘口袋检测的新型纹状体富含蛋白酪氨酸磷酸酶（STEP）抑制剂的发现，STEP是多种神经精神疾病的潜在药物靶点。通过结合使用分子动力学模拟和以片段为中心的地形测绘，我们识别出了短暂开放的隐秘口袋，并通过基于结构的虚拟筛选识别出了 12 个新的 STEP 抑制支架。定点诱变验证了 ST3 与预测的隐秘口袋的结合。此外，最有效和选择性的抑制剂可以调节 PC12 细胞中 ERK1/2 和 Pyk2 的磷酸化。