Data for: Mechanistic Insight into Chaperone GRP78 Protein Inhibition: Bio-Informatics Perspective

Glucose-regulation protein 78, GRP78, belongs to the HSPA protein family, ATP-dependent chaperones engagedin an unfolded protein response and prevention from the accumulation of misfolded proteins. As such, GRP78 is espe-cially important in highly proliferating cells, and often up-regulated in tumors. Because of that, GRP78 is marked asa potential protein target to treat various cancers, however, the high sequence similarity among HSPA family membershinders the drug-design process. So far, many research groups have reported promising small molecules capable tocompete with ATP, a natural ligand of GRP78, binding stronger within the nucleoside binding pocket. Despite largevariability, they are still hardly specific. To overcome it we investigated the molecular interactions which stabilizesligand within GRP78 binding pocket. For that, we enrolled bio-informatics tool and investigated how the structuralproperties of known GRP78 inhibitors corresponds with their binding affinity. Molecular docking calculations revealedthe most common interaction sites within a binding site and the potential interacting spots outside the canonical pocket.Importantly, some of those alternative positions involve residues, which are less conserved among HSPA protein family.Those can be further discriminated based on the main interactions; H-bonds, aromatic or cation-π. On the other hand,molecular dynamics simulations tracked the interaction evolution over time, and compared them to the intra-proteincontact network in the apo state. Moreover, conformational fluctuations observed in MD simulations revealed the roleof the entropy for different binding affinity among complexes with similar protein-ligand interactions pattern. Confor-mational studies uncovered also two binding sites with antagonistic allosteric effect identifying promising avenues fordevelopment of new GRP78 modulators.