Drug repurposing in Ras/Raf/Mek/ERK signaling pathway

Ras/Raf/MEK/ERK signaling pathway regulates cell growth, division, and differentiation. In this work, we focus on drug repurposing in the Ras/Raf/MEK/ERK signaling pathway, considering structural similarities of protein-protein interfaces. The protein-protein complexes in this pathway are extracted from literature and the interfaces formed by physically interacting proteins are found via PRISM (a template-based protein-protein docking tool) if not available in Protein Data Bank. As a result, 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. Then, the Food and Drug Administration (FDA) approved drugs bound to the interfaces are proposed for the other protein-protein interfaces that are structurally similar. The results suggest that HIV protease inhibitors tipranavir, indinavir and saquinavir bind to Epidermal Growth Factor Receptor (EGFR) and Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3/HER3) interface. Tipranavir and indinavir also bind to EGFR and Receptor Tyrosine- Protein Kinase ErbB-2 (ERBB2/HER2) interface. Additionally, a drug used in Alzheimer's disease (galantamine) and an antinauseant for cancer chemotherapy patients (granisetron) can bind to RAF proto-oncogene serine/threonine-protein kinase (RAF1) and Serine/threonine-protein kinase B-raf (BRAF) interface. Hence, these drugs can be used for anti-tumor activities in cancer with future experimental validation.