当前研究旨在通过计算辅助分子设计和实验研究，设计具有抗增殖和抗肿瘤活性的咖喱素类似物抑制剂，针对BRCA1和TP53肿瘤蛋白，并研究其治疗潜力。计算上设计了四个咖喱素类似物，并预测了其药物相似性和药代动力学特性。通过分子对接对比了这些类似物与BRCA1和TP53肿瘤蛋白家族六个靶蛋白的结合能与咖喱素、标准药物环磷酰胺及其验证靶标的结合能。选定的对接复合物稳定性通过分子动力学模拟（MDS）和MMGBSA计算进行了确认。最佳对接类似物进行了化学合成、表征，并用于DLA、EAC和C127I细胞系的体外细胞毒性筛选。在瑞士白化小鼠上进行了体内抗肿瘤研究。研究结果显示，设计的类似物符合药物相似性和药代动力学特性，与选择的靶标相比，它们具有更好的结合亲和力。在类似物中，NLH与BRCA1-BRCT-c结构域（TG3; 结合能 -8.3 kcal/mol）之间的相互作用显著，与咖喱素（结合能 -6.19 kcal/mol）和环磷酰胺（结合能 -3.8 kcal/mol）及其常规底物（TG7）的相互作用相比。MDS和MM/GBSA研究表明，NLH-TG3复合物的结合自由能（-61.24 kcal/mol）优于环磷酰胺-TG7复合物（-21.67 kcal/mol）。体外细胞毒性研究显示，NLH对肿瘤细胞系具有显著的抗增殖活性。体内研究表明，NLH具有抑制肿瘤的潜力。因此，新合成的咖喱素类似物可能用于开发针对乳腺癌的新型治疗药物。版权所有 © 2023 Elsevier B.V. 保留所有权利。

The current study aimed to design novel curcumin analogue inhibitors with antiproliferative and antitumor activity towards BRCA1 and TP53 tumor proteins and to study their therapeutic potential by computer-aided molecular designing and experimental investigations. Four curcumin analogues were computationally designed and their drug-likeness and pharmacokinetic properties were predicted. The binding of these analogues against six protein targets belonging to BRCA1 and TP53 tumor proteins were modelled by molecular docking and their binding energies were compared with that of curcumin and the standard drug cyclophosphamide and its validated target. The stabilities of selected docked complexes were confirmed by molecular dynamic simulation (MDS) and MMGBSA calculations. The best-docked analogue was chemically synthesized, characterized, and used for in vitro cytotoxic screening using DLA, EAC, and C127I cell lines. In vivo antitumor studies were carried out in Swiss Albino Mice. The study revealed that the designed analogues satisfied drug-likeness and pharmacokinetic properties and demonstrated better binding affinity to the selected targets than curcumin. Among the analogues, NLH demonstrated significant interaction with the BRCA1-BRCT-c domain (TG3; binding energy -8.3 kcal/mol) when compared to the interaction of curcumin (binding energy -6.19 kcal) and cyclophosphamide (binding energy -3.8 kcal/mol) and its usual substrate (TG7). The MDS and MM/GBSA studies revealed that the binding free energy of the NLH-TG3 complex (-61.24 kcal/mol) was better when compared to that of the cyclophosphamide-TG7 complex (-21.67 kcal/mol). In vitro, cytotoxic studies showed that NLH demonstrated significant antiproliferative activities against tumor cell lines. The in vivo study depicted NLH possesses the potential for tumor inhibition. Thus, the newly synthesized curcumin analogue is probably used to develop novel therapeutic agents against breast cancer.Copyright © 2023 Elsevier B.V. All rights reserved.