Discovery of Potent Parthenolide Derivatives Against Triple‐Negative Breast Cancer Using 3D‐QSAR, Virtual Screening, and Molecular Dynamics

Abstract Triple‐negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited treatment options, posing a significant threat to women's health. Casein kinase IIα (CK2) has emerged as a promising therapeutic target, as its inhibition is associated with decreased tumor growth. Meanwhile, parthenolide (PTN) shows potential when used in combination therpies against TNBC. This study explored novel PTN derivatives for managing TNBC. A pharmacophore hypothesis and a 3D‐QSAR model were developed based on the inhibitory concentrations of 61 PTN derivatives. The resulting 3D‐QSAR AAHHR_1 model demonstrated strong statistical performance (R 2 = 0.907, Q 2 = 0.801), and its robust predictive capability was confirmed through external validation (R 2 = 0.803). The model passed Tropsha's and Y‐Randomization tests, underscoring its reliability. By employing the top pharmacophore models as 3D queries, 40,006 PTN derivatives were screened from PubChem database, leading to the identification of 6 promising candidates based on their interactions with CK2. Following a thorough evaluation of their physicochemical properties, the compound CID_60143205 emerged as the most promising candidate. Subsequent 200 ns‐molecular dynamics simulation and free energy calculations verified that the CID_60143205‐CK2 complex maintained stablity. These findings indicate that the newly identified hits could serve as valuable leads for CK2 inhibition in the treatment of TNBC.