Breast 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. The 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). The 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.

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一些 2-苯胺基嘧啶衍生物作为抗三阴性乳腺癌药物的计算机研究

乳腺癌是全球主要的健康问题，也是女性癌症相关死亡的第二大原因。据预测，全球每年检测到大约 1 到 130 万例乳腺癌病例。三阴性乳腺癌 (TNBC) 被描述为缺乏人类表皮生长因子受体 2 (HER2)、雌激素受体 (ER) 和孕激素受体 (PR)。TNBC 定期转移到中枢神经系统和肺部。与非 TNBC 患者相比，由于非增强型抑制剂化合物，这种转移作用降低了 TNBC 患者的预期寿命。本研究的目的是通过 QSAR 和分子对接研究等 in silico 研究，探索 2-苯胺基嘧啶衍生物对三阴性癌细胞系 MDA-MB-468 的抗增殖活性，以进一步设计和开发新的抗乳腺癌药物。药效高，毒性低。定量构效关系 QSAR 模型预测化合物的生物活性，分子对接研究包含衍生物（配体）和甲状腺激素（TRβ1）（受体）之间的相互作用。模型4被选为统计评估的最佳模型；R2 = 0.8760，R2adj = 0.8451，Q2 = 0.6141，R2pred 为 0.5390。从 QSAR 模型的外部验证来看，模型参数的平均效应系数表明，降低（VR1_Dzv 和 MOMI-R）和增加（SpMin1_Bh 和 C3SP3）会增加化合物的抗增殖活性（pIC50）。分子对接研究表明，配体 15 和 18 与甲状腺激素受体 (TRβ1) 的对接评分最高，分别为 - 7.3 和 - 7.4 kcal/mol。配体的对接评分优于标准抗乳腺癌药物吉非替尼 (- 5.3 kcal/mol)。结果表明，模型4可用于开发新的2-苯胺基嘧啶衍生物，具有更好的抗乳腺癌预测活性和性能。已经证明一些系列的 2-苯胺基嘧啶衍生物化合物与受体紧密结合，稳定受体（TRβ1），这从受体-配体相互作用中可以看出，这些化合物将作为最有希望的 TRβ1 抑制剂。这表明药物研究人员在设计和开发新的抗三阴性乳腺癌药物方面取得了突破。