Exploring Molecular Contacts of MUC1 at CIN85 Binding Interface to Address Future Drug Design Efforts

Abstract

The modulation of protein-protein interactions (PPIs) by small molecules represents a valuable strategy for pharmacological intervention in several human diseases. In this context, computer-aided drug discovery techniques offer useful resources to predict the network of interactions governing the recognition process between protein partners, thus furnishing relevant information for the design of novel PPI modulators. In this work, we focused our attention on the MUC1-CIN85 complex as a crucial PPI controlling cancer progression and metastasis. MUC1 is a transmembrane glycoprotein whose extracellular domain contains a variable number of tandem repeats (VNTRs) regions that are highly glycosylated in normal cells and under-glycosylated in cancer. The hypo-glycosylation fosters the exposure of the backbone to new interactions with other proteins, such as CIN85, that alter the intracellular signalling in tumour cells. Herein, different computational approaches were combined to investigate the molecular recognition pattern of MUC1-CIN85 PPI thus unveiling new structural information useful for the design of MUC1-CIN85 PPI inhibitors as potential anti-metastatic agents.

A Computer-Based Methodology to Design Non-Standard Peptides Potentially Able to Prevent HOX-PBX1-Associated Cancer Diseases

“…Although 3D structures of the ternary complex HOX-PBX-DNA have been experimentally solved, the drug discovery process for this protein-protein interaction (PPI) has met some issues typical of targeting a PPI through designing potential effective small molecule inhibitors [ 38 , 39 ]. However, an accepted strategy is to target the HOX-PBX binding interface at the highly conserved residues involving HOX hexapeptide and exploiting the hydrophobic nature of the PBX protein binding pocket.…”