We focus on drug repurposing in the Ras signaling pathway, considering structural similarities of protein–protein interfaces. The interfaces formed by physically interacting proteins are found from PDB if available and via PRISM (PRotein Interaction by Structural Matching) otherwise. The structural coverage of these interactions has been increased from 21 to 92% using PRISM. Multiple conformations of each protein are used to include protein dynamics and diversity. Next, we find FDA-approved drugs bound to structurally similar protein–protein interfaces. The results suggest that HIV protease inhibitors tipranavir, indinavir, and saquinavir may bind to EGFR and ERBB3/HER3 interface. Tipranavir and indinavir may also bind to EGFR and ERBB2/HER2 interface. Additionally, a drug used in Alzheimer's disease can bind to RAF1 and BRAF interface. Hence, we propose a methodology to find drugs to be potentially used for cancer using a dataset of structurally similar protein–protein interface clusters rather than pockets in a systematic way.

考虑到蛋白质-蛋白质界面的结构相似性，我们专注于 Ras 信号通路中的药物再利用。如果有的话，可以从 PDB 中找到由物理相互作用的蛋白质形成的界面，否则通过 PRISM（通过结构匹配进行蛋白质相互作用）找到。使用 PRISM，这些相互作用的结构覆盖率已从 21% 增加到 92%。每种蛋白质的多种构象用于包括蛋白质动力学和多样性。接下来，我们发现 FDA 批准的药物与结构相似的蛋白质-蛋白质界面结合。结果表明，HIV 蛋白酶抑制剂替拉那韦、茚地那韦和沙奎那韦可能与 EGFR 和 ERBB3/HER3 界面结合。替拉那韦和茚地那韦也可能与 EGFR 和 ERBB2/HER2 界面结合。此外，一种用于治疗阿尔茨海默病的药物可以与 RAF1 和 BRAF 界面结合。因此，我们提出了一种方法，以系统的方式使用结构相似的蛋白质-蛋白质界面簇而不是口袋的数据集来寻找可能用于癌症的药物。