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Background Poly (ADP-ribose) polymerase 12 (PARP12) plays a crucial role in DNA damage response (DDR) through DNA repair, maintaining genomic stability. Mutations in PARP12 contribute to genomic instability, leading to cancer progression. Targeting PARP12 mutants with small molecule inhibitors offers a promising therapeutic strategy.Objective This study aims to identify potent inhibitors for PARP12 mutants using molecular docking-based virtual screening from the National Cancer Institute (NCI) compound library, followed by molecular dynamics (MD) simulations to validate binding stability.Methods Homology models of human PARP12 mutants were developed for virtual screening. The top-scoring compounds were refined through molecular docking, and their stability was analyzed using all-atomistic MD simulations. Binding free energy (MMGBSA) calculations and structural dynamics assessments, including RMSD, RMSF, RoG, and SASA, were conducted to evaluate the drug-receptor interactions.Results Three promising inhibitors, NCI-32743, NCI-32982, and NCI-659779, demonstrated high binding affinity and stability with PARP12 mutants. These compounds showed significant inhibitory potential, maintaining strong interactions with the target protein throughout the simulation period. ADMET and pharmacokinetic analyses confirmed their drug likeness and potential for further development.Conclusion The identified inhibitors exhibit strong potential for targeting PARP12 mutants in cancer therapy. Further in vitro and in vivo studies are required to confirm their efficacy and therapeutic viability for clinical applications.