Discovery of Phthalazine Derivatives as New PARP1 Inhibitors Through 3D-QSAR, Molecular Docking, and MD Studies
| Author | Tahereh Sedghamiz | en |
| Author | Somayeh Asgharpour Hasan Kiyadeh | en |
| Author | Fatemeh Moosavi | en |
| Author | Alireza Poustforoosh | en |
| Issued Date | 2026-12-31 | en |
| Abstract | Background: Poly(ADP-ribose) polymerase 1 (PARP1) is a well-established therapeutic target in cancer owing to its critical role in DNA damage repair. In this study, we combined structure-based and ligand-based computational approaches to identify and optimize phthalazine derivatives as new PARP1 inhibitors. Objectives: This study aimed to highlight the potential of computationally guided drug discovery in developing novel phthalazine-based PARP1 inhibitors and to support their candidacy as anticancer agents. Methods: A 3D-QSAR model was generated using Phase and demonstrated strong statistical performance (R2 = 0.89, Q2 = 0.701). ADME/T predictions further confirmed the drug-like properties of the optimized compounds. A set of intrinsic PARP1 inhibitors was docked using Glide XP, and detailed interaction analyses were performed. To further validate the docking results, molecular dynamics (MD) simulations were conducted on the top three compounds. Results: Contour map analysis indicated that steric, electrostatic, hydrogen-bond donor/acceptor, and hydrophobic fields play important roles in determining biological activity. Favorable and unfavorable regions near functional groups such as carbonyls, amines, and aromatic rings provided guidance for designing more potent derivatives. Several newly designed phthalazine derivatives showed improved docking scores and formed more stabilizing interactions than reference inhibitors such as fluzoparib. Among them, compounds 42 and 63 displayed the strongest binding affinities and robust interaction profiles, including multiple conserved hydrogen bonds and π–π stacking interactions. The MD trajectories demonstrated stable binding within the PARP1 active site, with persistent hydrogen bonds, particularly those with Ser904 and Gly863, supporting the reliability of the docking and QSAR findings. Conclusions: The integrated QSAR, docking, and MD approaches provide strong evidence for the potential of phthalazine derivatives as novel PARP1 inhibitors and identify promising candidates for further experimental validation in anticancer drug discovery. | en |
| DOI | https://doi.org/10.5812/ijpr-169970 | en |
| URI | https://brieflands.com/journals/ijpr/articles/169970 | en |
| Publisher | Brieflands | en |
| Title | Discovery of Phthalazine Derivatives as New PARP1 Inhibitors Through 3D-QSAR, Molecular Docking, and MD Studies | en |
| Type | Research Article | en |