Abstract C007: Expanding Chemical Space: Discovery of Novel PARP Inhibitors Using Diverse Pharmacophore-Based Screening

Abstract Introduction: The discovery of new cancer therapies has shifted from traditional high-throughput screening to more efficient computational methods. This study presents an integrated virtual screening approach combining ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) to identify novel poly(ADP-ribose) polymerase 1 (PARP1) inhibitors. By combining these complementary methods, we enhance hit identification and prioritization of novel PARP inhibitors. Methods: A multi-reference pharmacophore approach was employed using 10 nanomolar PARP1 inhibitors serving as references. The virtual screening of the 4M Enamine Screening database was performed against 12 pharmacophore model variants. This screening process yielded 1,792 ligands that demonstrated comparable docking scores to the reference PARP inhibitor, olaparib. These ligands were energy-minimized and subsequently ranked according to their binding free energy, which was calculated using the MMGBSA method. The top 50 candidates were then subjected to a reverse screening procedure to evaluate their selectivity for PARP1 over PARP2. The 12 most promising compounds, based on both predicted efficacy and selectivity, were selected for three independent 100 ns molecular dynamics simulations, alongside with olaparib. Results: Among the evaluated compounds, PH-PARP06 emerged as a strong PARP1 inhibitor, with a final binding free energy lower than olaparib. Regarding the molecular dynamics results, PH-PARP06 demonstrated an enhancement in complex stability and a better average binding free energy in comparison to the reference. Besides, experimental validation in breast cancer cell demonstrated that PH-PARP06 exhibited inhibitory activity in vitro comparable to the clinically approved PARP inhibitor olaparib, effectively induced DNA damage response markers, such as cleaved PARP1 and phosphorylated H2AX, and impaired DNA repair processes selectively in cancer cells. Additionally, PH-PARP06 treatment resulted in G2/M cell cycle arrest and apoptosis, indicating its potential as an effective anti-cancer agent. PH-PARP06 also demonstrated competitive IC50 values for both PARP1 and PARP2, warranting further exploration of its selectivity profile. Conclusion: In this study, we combine pharmacophore-based virtual screening with molecular docking and molecular dynamics simulations to improve hit identification and binding prediction. To further refine this methodology, we are incorporating atomistic modeling and MD-based evaluation to capture the dynamic behavior of ligand–target interactions at high resolution. Citation Format: Lucía Paniagua-Herranz, Natàlia DeMoya-Valenzuela, Cristian Privat, Cristina Díaz-Tejeiro, Pawel Gancarski, Elisa Poyatos-Racionero, Cristina Nieto-Jiménez, Pablo Rodríguez-Olmedo, Pedro Pérez Segura, Alberto Ocana. Expanding Chemical Space: Discovery of Novel PARP Inhibitors Using Diverse Pharmacophore-Based Screening [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C007.