Conformational diversity and protein-protein interface clusters help drug repurposing in Ras/Raf/MEK/ERK signaling pathway

Abstract

ABSTRACTRas/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 complexes in this pathway are extracted from literature and interfaces formed by physically interacting proteins are found via PRISM (PRotein Interaction by Structural Matching) 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 and diversity. Next, we find FDA-approved drugs bound to additional structurally similar protein-protein interfaces. The results suggest that HIV protease inhibitors tipranavir, indinavir and saquinavir may bind to Epidermal Growth Factor Receptor (EGFR) and Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3/HER3) interface. Tipranavir and indinavir may 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, we propose an algorithm to find drugs to be potentially used for cancer. As a summary, we propose a new strategy of using a dataset of structurally similar protein-protein interface clusters rather than pockets in a systematic way.Significance statementThis work focuses on drug repurposing in the Ras/Raf/MEK/ERK signaling pathway based on structural similarities of protein-protein interfaces. The Food and Drug Administration approved drugs bound to the protein-protein interfaces are proposed for the other interfaces using protein-protein interface clusters based on structural similarities. Moreover, the structural coverage of protein complexes of physical interactions in the pathway has been increased from 21% to 92% using multiple conformations of each protein to include protein dynamics.