In silico studies of some 2-anilinopyrimidine derivatives as anti-triple-negative breast cancer agents

Abstract

BackgroundBreast cancer is a major form of health problem on the globe and the second cause of death related to cancer amidst women. A prediction of about 1 to 1.3 million cases on cancer of the breast are detected yearly globally. Triple-negative type of breast cancers (TNBCs) are described by the lack of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR). TNBCs metastasize to the central nervous system and lungs regularly. Such metastatic actions reduce the life expectancy of patients with TNBC than patients with non-TNBC due to non-enhanced inhibitor compounds. The purpose of this research was to explore the anti-proliferative activities of 2-anilinopyrimidine derivatives against triple-negative cancer cell line MDA-MB-468 via in silico studies like QSAR and molecular docking studies to further design and develop new anti-breast cancer drug with high potency and low toxicity.ResultsThe quantitative structure–activity relationship QSAR model predicts the bioactivities of the compounds, and molecular docking studies comprehend the interaction between the derivatives (ligand) and thyroid hormone (TRβ1) (receptor). Model 4 was chosen as the best model from the statistical assessment; R2 = 0.8760, R2adj = 0.8451, Q2 = 0.6141, and R2pred of 0.5390. From the external validation of the QSAR model, the coefficient of the mean effect on the model parameters indicates that decreasing (VR1_Dzv and MOMI-R) and increasing (SpMin1_Bh and C3SP3) would increase the anti-proliferative activities (pIC50) of the compounds. The molecular docking studies revealed that ligands 15 and 18 had the highest docking scores of − 7.3 and − 7.4 kcal/mol with thyroid hormone receptor (TRβ1). The ligands had docking scores better than the standard anti-breast cancer drug gefitinib (− 5.3 kcal/mol).ConclusionsThe results indicate that model 4 can be used in developing new 2-anilinopyrimidine derivatives, with better anti-breast cancer prediction activity and performance. It was proved that some series of 2-anilinopyrimidine derivative compounds bind tightly to the receptor, stabilizing the receptor (TRβ1) which is evident from the receptor–ligand interactions, and these compounds would serve as the most promising inhibitors against TRβ1. This shows a breakthrough for pharmaceutical researchers in designing and developing new anti-triple-negative breast cancer drugs.