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Abstract
Protein-protein interactions (PPIs) play a pivotal role in the regulation of many physiological processes. The dysfunction of some PPIs interactions led to the alteration of different biological pathways causing various diseases including cancer. In this context, the inhibition of PPIs represents an attractive strategy for the design of new antitumoral agents. In recent years, computational approaches were successfully used to study the interactions between proteins, providing useful hints for the design of small molecules able to modulate PPIs. Targeting PPIs presents several challenges mainly due to the large and flat binding surface that lack the typical binding pockets of traditional drug targets. Despite these hurdles, substantial progress has been made in the last decade resulting in the identification of PPI modulators where some of them even found clinical use. This study focuses on MUC1-CIN85 PPI which is involved in the migration and invasion of cancer cells. Particularly, we investigated the presence of druggable binding sites on the CIN85 surface which provided new insights for the structure-based design of novel MUC1-CIN85 PPI inhibitors as anti-metastatic agents.
Highlights
In the crowded cellular environment, many biological processes such as cellular growth, DNA replication, transcription, translation, and signal transduction are regulated by protein-protein interactions (PPIs) [1]
The evolution of the root mean square deviations (RMSD) of the protein backbone was calculated and plotted as depicted in 175 ns for about 30 ns after which the system remained stable for the rest of the simulation
PPI involved in the formation of metastasis in cancer cells
Summary
In the crowded cellular environment, many biological processes such as cellular growth, DNA replication, transcription, translation, and signal transduction are regulated by protein-protein interactions (PPIs) [1]. Targeting PPIs by small molecules presents several challenges associated with the large and flat binding surface and the absence of well-defined cavities able to bind low molecular weight compounds with high affinity [3]. PPIs lack natural substrates or effectors that could serve as a starting point for the design of new ligands [4]. Despite these difficulties, several PPI inhibitors have been reported in the last decade and some of them were approved for clinical usage or are currently investigated in clinical trials [5]. Due to the flexibility of the protein interface, the opening of transient pockets, that might provide suitable sites for small molecules, was observed [9,10,11]
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