Targeting Poly (ADP-ribose) polymerase-1 (PARP-1) for DNA repair mechanism through QSAR-based virtual screening and MD simulation.

Poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme in the base excision repair pathway, crucial for maintaining genomic stability by repairing DNA breaks. In cancers with mutations in DNA repair genes, such as BRCA1 and BRCA2, PARP-1 activity becomes essential for tumor cell survival, making it a promising target for therapeutic intervention. This study employs QSAR modeling, virtual screening, and molecular dynamics (MD) simulations to identify potential PARP-1 inhibitors. A dataset of inhibitors was analyzed using 12 molecular fingerprint descriptors to develop robust QSAR models, with the optimal model based on the CDK descriptor achieving R² = 0.96, Q²_CV = 0.78, and Q²_Ext = 0.80. The model was applied to virtually screen three chemical libraries-ZINC, FDA, and NPA-identifying promising candidates for PARP-1 inhibition. Molecular docking revealed that compounds ZINC13132446, Z2037280227, and NPC193377 have strong binding affinity for the PARP-1 active site. MD simulations and MM-PBSA confirmed the stability of these complexes, with Z2037280227 and NPC193377 exhibiting the most stable interactions. These results underscore the potential of targeting PARP-1 as a therapeutic strategy for cancers with homologous recombination deficiencies, including prostate, breast, and ovarian cancer, particularly in patients with DNA repair deficiencies.