Abstract
BRCA-driven cancers remain a challenge worldwide due to PARP1's critical role in DNA repair and cancer cell survival. Therefore, PARP1 is an important target for the treatment of BRCA-related cancers. However, current PARP1 inhibitors have toxicity and resistance issues, highlighting the need for new scaffolds. In search of compounds, Tanshinone I emerged as a promising candidate with known anticancer properties. However, its poor solubility and bioavailability, as well as its unknown interaction with PARP1, limit its clinical potential. In this study, Tanshinone I was modified to enhance its solubility and bioavailability by introducing carboxamide and pyrrolidine moieties. We used integrated computational methods to evaluate the potential of the new compounds. Docking experiments demonstrated that two compounds, TAN1 and TAN6, had a strong affinity for the PARP1 active site (- 11.8 and - 10.9 kcal/mol). The ADME/T analysis predicts their improved solubility and bioavailability. In addition, molecular dynamics and MM/PBSA simulations report TAN1 with lower RMSD/RMSF and interact with the ART site, whereas TAN6 shows higher binding free energy (-45.06 kcal/mol) compared to TAN1 (-41.61 kcal/mol) and is close to olaparib (-45.64 kcal/mol) and interacts with HD and the ART site. These differences reflect distinct aspects of protein-ligand interaction and stability. Suggesting that TAN1 and TAN6 are compounds that can interact with PARP1; further replication and experimental validation would be necessary to confirm these findings quantitatively.