Computational Chemistry Advances in the Development of PARP1 Inhibitors for Breast Cancer Therapy

Poly (ADP-ribose) polymerase 1 (PARP1) is an important enzyme that plays a central role in the DNA damage response, facilitating repair of single-stranded DNA breaks via the base excision repair (BER) pathway and thus genomic integrity. Its therapeutic relevance is compounded in breast cancer, particularly in BRCA1 or BRCA2 mutant cancers, where compromised homologous recombination repair (HRR) leaves a synthetic lethal dependency on PARP1-mediated repair. This review comprehensively discusses the recent advances in computational chemistry for the discovery of PARP1 inhibitors, focusing on their application in breast cancer therapy. Techniques such as molecular docking, molecular dynamics (MD) simulations, quantitative structure–activity relationship (QSAR) modeling, density functional theory (DFT), time-dependent DFT (TD-DFT), and machine learning (ML)-aided virtual screening have revolutionized the discovery of inhibitors. Some of the most prominent examples are Olaparib (IC₅₀ = 5 nM), Rucaparib (IC₅₀ = 7 nM), and Talazoparib (IC₅₀ = 1 nM), which were optimized with docking scores between −9.0 to −9.3 kcal/mol and validated by in vitro and in vivo assays, achieving 60–80% inhibition of tumor growth in BRCA-mutated models and achieving up to 21-month improvement in progression-free survival in clinical trials of BRCA-mutated breast and ovarian cancer patients. These strategies enable site-specific hopping into the PARP1 nicotinamide-binding pocket to enhance inhibitor affinity and specificity and reduce off-target activity. Employing computation and experimental verification in a hybrid strategy have brought next-generation inhibitors to the clinic with accelerated development, higher efficacy, and personalized treatment for breast cancer patients. Future approaches, including AI-aided generative models and multi-omics integration, have the promise to further refine inhibitor design, paving the way for precision oncology.