Computer-Aided Drug Design of Small Molecule Inhibitors of the ERCC1-XPF Protein-Protein Interaction.

The heterodimer of DNA excision repair protein ERCC-1 and DNA repair endonuclease XPF (ERCC1-XPF) is a 5 '-3 ' structure-specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1-XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum-based and cross-linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1-XPF interaction (Molecular Pharmacology, 84, 2013 and 12), to improve its binding to the target. We followed a multi-step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5, showed an improved half-maximum inhibitory concentration (IC50) value of 0.49 mu M for the inhibition of ERCC1-XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1-XPF complex.