Consensus virtual screening of approved and late-phase clinical drugs identifies candidate inhibitors of the WRN helicase for microsatelliteunstable cancers

The Werner syndrome ATP-dependent helicase (WRN) is a synthetic-lethal dependency in cancers with microsatellite instability (MSI-H), yet only two inhibitor chemotypes have entered clinical development (HRO761 and VVD-133214/VVD-214), both discovered de novo. Approved and late-phase clinical drugs with plausible WRN binding remain unexplored, leaving a large repurposing opportunity open. This preprint presents a consensus virtual screening campaign against the allosteric helicase-domain pocket of WRN (PDB 7GQU) using the open-source tomdok pipeline. A library of 3,369 approved and Phase-III compounds (ChEMBL 37), filtered from 4,342 SQL-filtered rows and parent-deduplicated, was screened with a three-engine consensus protocol (GNINA, AutoDock Vina, LeDock) coupled to dual affinity/CNN-pose-confidence thresholds and data-driven safety annotation (hERG liability from ChEMBL KCNH2 bioactivity, PAINS, withdrawn status). Self-docking of the co-crystallised inhibitor reproduced the native pose (best-pose RMSD 1.46 A, PASS at the 2.0 A threshold). The funnel retained 66 primary hits and 60 consensus hits: 43 carried no safety liabilities (CLEAN) and 17 were flagged (hERG, PAINS or Lipinski violations). Top CLEAN candidates include the NPC1L1 inhibitor ezetimibe (approved; GNINA32 -10.35, Vina -10.08, CNN 0.94) together with its Phase-III analogue hyzetimibe, the dopaminergic partial agonist bifeprunox (strongest CLEAN binder, -10.92/-10.88 with near-perfect inter-engine agreement), and a coherent cluster of approved piperazine antihistamines and antimuscarinics (cinnarizine, meclizine, buclizine, trospium). The data-driven hERG layer independently re-derived known QT liabilities (pimozide, astemizole, mizolastine, sildenafil) while sparing structurally related CLEAN compounds. We provide a ranked, safety-annotated shortlist of repurposing candidates for WRN inhibition in MSI-H cancers, ready for biochemical and cellular validation. Companion data deposit (consensus tables, ADMET profiles, 3D poses, figures, full execution log, supplementary bundle): Zenodo, doi:10.5281/zenodo.22109731. Pipeline: tomdok, https://github.com/NikTomSik/tomdok (MIT). Code archive: Zenodo, doi:10.5281/zenodo.22104868.