Energy Landscape Mapping–Guided Rational Design of Coumarin‐Based PARP‐1 Inhibitors

Abstract Poly(ADP‐ribose) polymerase‐1 (PARP‐1) is vital for DNA repair, making it a key anticancer target. This study uses a structure‐based computational approach to design and evaluate coumarin–thiazolidine–4–one and coumarin–triazole hybrids targeting the catalytic ART domain of PARP‐1. Docking and molecular dynamics simulations were conducted using Olaparib‐bound (7KK4) and JA2131‐bound (6OA3) PARP‐1 structures. Among the designed compounds, CU‐TZD‐20 showed the highest binding affinity, with docking scores of −11.38 kcal/mol (7KK4) and −11.98 kcal/mol (6OA3), outperforming Olaparib (–9.38 kcal/mol) and JA2131 (–6.92 kcal/mol). MM‐GBSA binding energy for CU‐TZD‐20 was −118.32 kcal/mol, compared to −62.62 kcal/mol for Olaparib. MD simulations revealed reduced RMSF (∼5.2 Å) and minimal center of mass fluctuations, indicating enhanced stability, while maintaining the residue decomposition analysis from −45 to −20 kcal/mol with key residues. Key interactions were identified with Gly863, Asp770, Ser904, and Tyr896 (7KK4) and Tyr795, Phe902, Ile726 (6OA3). Energy landscape and PCA analyses showed lower conformational flexibility and stable binding. Free energy landscape (FEL) analysis further confirmed a more stable conformational basin for CU‐TZD‐20. Overall, CU‐TZD‐20 demonstrates strong binding, structural stability, and potential as a lead PARP‐1 inhibitor, warranting experimental validation.