p53 Y220C是不同人类癌症中观察到的最常见的结构突变之一。在残基酪氨酸(Tyr)被半胱氨酸(Cys)取代的情况下，p53 DNA结合结构域易受溶剂进入结构域的疏水核心的影响，从而使p53不稳定，并导致其失去抑制肿瘤的活性。该突变在DNA结合结构域的S3/S4和S7/S8环之间创造了一个结构缺口，可被小分子靶向。研究表明，合成和天然化合物可以与该缺口结合，并恢复突变体p53Y220C的结构和功能至野生型。在我们之前的研究中，我们已经发现姜黄素可救回携带基因突变的胰腺癌细胞系BxPC-3中突变体p53Y220C的功能。在本研究中，我们探索了六个结构类似于姜黄素的黄酮类化合物，如芹菜素(Apigenin)、孤零甘露糖苷(Isoliquiritigenin)、甘草苷(Liquiritigenin)、黄酮(Luteolin)、甲基云南野葛酮A (MPA)和甲基云南野葛酮B (MPB)，通过分子对接、分子动力学模拟和细胞毒性试验来测试它们修复p53Y220C的潜力。在MD模拟后的二级结构分析表明，这些化合物可以稳定突变体p53 DNA结合结构域至野生型。在基于细胞的细胞毒性研究中，使用携带p53Y220C的BxPC-3细胞系，化合物MPA和MPB在100µM浓度下显示了75%的细胞死亡。我们提出，MPA和MPB黄酮类化合物具有恢复p53Y220C的治疗潜力，并可作为联合治疗来减轻剂量负担。由Ramaswamy H. Sarma通讯。

The p53 Y220C is one of the most frequently observed structural mutants in various human cancers. The substitution of residue Tyr to Cys makes the p53 DNA binding domain susceptible to solvent entry into the hydrophobic core of the domain thereby destabilizing p53, which results in loss of its tumor suppressor activity. The mutation creates a structural crevice at the region between S3/S4 and S7/S8 loops in the DNA binding domain which can be targeted by small molecules. Studies have shown that the synthetic and natural compounds could bind to this crevice and restore the structure and function of the mutant p53Y220C to the wild type. In our previous study, we have shown Curcumin could rescue the function of mutant p53Y220C in pancreatic cancer cell line BxPC-3 harboring genomic mutation. In this study, we explored six flavonoids structurally similar to Curcumin such as Apigenin, Isoliquiritigenin, Liquiritigenin, Luteolin, Methylophiopogonanone A (MPA), and Methylophiopogonanone B (MPB) to test their potency to restore p53Y220C by molecular docking, molecular dynamics simulations and cytotoxicity assay. The secondary structure analysis after the MD simulations suggested that these compounds could stabilize the mutant p53 DNA binding domain to the wild type. In the cell-based cytotoxicity studies using p53Y220C harbouring BxPC-3 cell lines, the compounds MPA and MPB showed 75% cell death at 100 µM concentration. We proposed that the flavonoids MPA and MPB have the therapeutic potential to restore p53Y220C and could be used as a combinatorial therapy to reduce the dosage burden.Communicated by Ramaswamy H. Sarma.