In silico Discovery of Candidate Inhibitors of C11orf54 - HSC70 Interaction for Selective Suppression of RAD51-dependent DNA Repair in Cancer

Abstract

C11orf54 (PTD012) has been implicated in cancer cell survival by blocking HSC70-mediated degradation of HIF1A, thereby sustaining RRM2-driven dNTP supply for RAD51-dependent homologous recombination. This research integrated computational strategies to define the C11orf54–HSC70 interface, identify energetic hotspots, and nominate disruptor ligands of this protein–protein interaction (PPI). An AlphaFold model of HSC70’s substrate-binding domain was relaxed by restrained MD and docked to the experimentally solved C11orf54 structure (PDB 1XCR) using HADDOCK 2.4, with the KFERQ motif specified as active. Interface residues from top clusters were analyzed and subjected to DrugScore PPI Alanine scanning to quantify energetic contributions. A 40,640-compound Enamine PPI library was screened with AutoDock Vina against the predicted interface; hits were filtered by affinity (<-8.0 kcal·mol⁻¹) and contacts with computational hotspots. Docking revealed a reproducible core interface centered on residues spanning Val72–Glu86 and a distal region around Asp304–Lys307. Alanine scanning identified six hotspots (ASN73, LYS75, VAL77, GLN153, ASP304, LYS307). Virtual screening yielded multiple ligands that consistently engaged ASN73, ASP304, and LYS307; the top ten candidates were prioritized for follow-up. These results support the druggability of the C11orf54–HSC70 interface and provide concrete residue anchors and compound scaffolds for experimental validation and medicinal chemistry optimization toward selective inhibitors of C11orf54-addicted tumors.