PARP-1 inhibitors in cancer therapy: design, molecular modeling, structure–activity relationships, and clinical advances

Abstract Poly (ADP-ribose) polymerase-1 (PARP-1) is an enzyme that plays a pivotal role in DNA repair and the maintenance of genomic stability. The discovery of synthetic lethality in tumors with homologous recombination deficiencies, particularly BRCA1/2 mutations, has validated PARP inhibitors as an important class of targeted anticancer agents. Several inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, are now clinically approved and have significantly demonstrated clinical benefit in selected patient populations. This review discusses the structural development of PARP-1 inhibitors from classical NAD analogues to newer non-NAD and dual-target compounds, with emphasis on structure–activity relationships (SAR) and molecular modeling studies. Key binding interactions within the PARP-1 catalytic domain and factors influencing selectivity and potency are highlighted, together with emerging strategies aimed at overcoming drug resistance and improving therapeutic effectiveness. Despite notable clinical success, challenges such as adverse effects, acquired resistance, and limited activity in certain tumor types remain. Continued research and development in rational drug design and biomarker-driven therapy is expected to enhance the precision and long-term benefit of PARP-1-targeted treatments.