Computational design and structural insights into quinazoline-based lead molecules for targeting PARP10 in cancer therapy

Abstract

Quinazoline scaffolds, a class of nitrogen-containing heterocyclic compounds, are considered a “privileged structure" in drug development due to their broad physiological activities and significant therapeutic potential. Many anti-breast cancer therapies are designed using this pharmacophore. Structural modifications such as halogen substitution and aromatic amino group insertion have been explored to improve the anticancer efficacy of quinazoline derivatives. Breast cancer continues to be the primary cause of cancer-related mortality among women, approximately 670,000 deaths globally in 2022, emphasizing the need for novel therapies. To combat multidrug resistance in breast cancer, new drug candidates targeting the Poly (ADP-ribose) polymerase (PARP) enzyme are being developed to improve chemotherapeutic efficacy and reduce toxicity. In this study, computational screening of 365 quinazoline derivatives was conducted to identify potential PARP inhibitors. Docking based screening identified three quinazoline scaffolds (RFAP77, RISA30, and RISAC) as top hits, demonstrating docking scores ranging from −8.41 to −9.31 kcal/mol and MM-GBSA binding free energy scores between −52.08 and −55.99 kcal/mol, compared to the reference approved inhibitor. ADMET analysis revealed favorable predicted drug-likeness profiles for the identified scaffolds. The structural stability of the docked PARP-ligand complexes was further investigated using molecular dynamics simulations (MDS). The computational simulations revealed significant conformational changes upon ligand binding, as evidenced by RMSD, RMSF, and hydrogen bond analyses. Essential dynamics analysis, including PCA-based FEL mapping, demonstrated energy minima profiles for all top docked PARP complexes. These computational findings highlight the potential of these scaffolds as promising candidates for further development as PARP inhibitors.