Computer- and NMR-aided design of small-molecule inhibitors of the Hub1 protein

Protein-protein interactions play a key role in cell homeostasis and physiological functions of the organisms. Consequently, their malfunction leads to diseases such as cancer, metastasis and neurodegeneration. The Hub1/Snu66 interaction is responsible for controlling alternative splicing through non-covalent binding to the HIND (Hub1-Interacting Domain) domain of the Snu66 spliceosomal protein. To better understand how Hub1 works in living organisms, we conducted a study to find small molecules that have an affinity for the Snu66 binding site of Hub1. The in silico investigation was based on global peptide modeling followed by high-resolution protein-peptide refinement. Docking analysis of nearly 200 molecules in the binding pocket of Hub1 is also described. Finally, Nuclear Magnetic Resonance fragment-based screening was used to confirm our findings.