2D-QSAR and Molecular Docking Studies of N-Substituted Rhodanine Derivatives as Potent Cytotoxic Agents

Abstract

HER2 positive breast cancer is most common malignancy in women globally. Aberrant behavior of HER2 kinase protein is a hallmark of tumorigenesis, and as a result it has been considered as an emerging potential drug target for breast cancer therapy. In the present investigation a series of N-substituted rhodanine derivatives (33 compounds) were subjected to 2D-QSAR studies with the aid of genetic algorithm (GA) method to identify the essential structural features that responsible for cytotoxic activity. Based on the results, the cytotoxic activity of N-substituted rhodanine derivatives can be successfully explained in terms of twodimensional (ATSC7v), and three-dimensional (geomRadius and RDF45i) descriptors. The obtained model was vigorously validated and passed all validation metrics (R2train = 0.913, R2adj = 0.899, Q2LOO = 0.870, R2test = 0.848). Importantly, the model quality was good based on mean absolute error (MAE) criteria and the results were consistent with proposed limits by Golbraikh and Tropsha. Molecular docking study of the active compounds (ligands 4, 16, and 27) revealed the formation of hydrogen and hydrophobic interactions within the active site of HER2 protein. Keywords: HER2 proteins, breast cancer, cytotoxic agents, rhodanine, molecular docking, 2DQSAR.