AI-aided virtual screening and biological evaluation for discovering new potential poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors.

Poly (ADP-ribose) polymerase-1 (PARP-1) is a key DNA repair enzyme targeted in cancer therapy. We developed an AI-assisted virtual screening workflow combining RG-MPNN for shape-based screening and PIGNet for docking rescoring to identify novel PARP1 inhibitors from an 18-million compound library. Five hits showed nanomolar activity, with Hit 1 exhibiting 8.03 nM IC₅₀ and a novel tricyclic scaffold. Comprehensive validation confirmed PARP1 inhibition, selective cytotoxicity in BRCA1-deficient cells, and favorable drug-like properties. Hit 1 represents a promising candidate for further development.