Nainggolan Sarah Ika, Rajuddin Rajuddin, Kamarlis Reno Keumalazia, Hambal Muhammad, Frengki Frengki
Graduate School of Mathematics and Applied Sciences, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia.
Department of Obstetrics and Gynecology, Division of Gynecological Endocrinology, Faculty of Medicine, Syiah Kuala University, Banda Aceh, Indonesia.
Vet World. 2025 Mar;18(3):715-730. doi: 10.14202/vetworld.2025.715-730. Epub 2025 Mar 31.
p53 is a critical tumor suppressor protein responsible for regulating the cell cycle and inducing apoptosis. Mutations in the gene, particularly in the DNA-binding domain, are frequently associated with various cancers due to the loss of transcriptional activity. Curcumin and its derivatives have demonstrated potential as p53 enhancers and reactivators of mutant p53. This study employs methods to evaluate the potential of curcumin derivatives to enhance wild-type p53 expression and restore the function of the p53 mutant R273H.
Curcumin and 20 derivatives were selected from PubChem for computational analysis. Their potential as p53 enhancers was assessed using Quantitative Structure-Activity Relationship (QSAR) analysis. Molecular docking was conducted to determine their binding affinities with wild-type and mutant p53 proteins, followed by molecular dynamics (MD) simulations to evaluate ligand-receptor stability. Pharmacokinetics and toxicity assessments were performed using predictive computational models to evaluate their drug-like properties.
QSAR analysis identified hexahydrocurcumin (probable activity [Pa]: 0.837) and tetrahydrocurcumin (Pa: 0.752) as the most potent p53 enhancers. Molecular docking revealed strong binding affinities for curcumin derivatives at key p53 binding residues, particularly through hydrogen bonds with His 273 of the R273H mutant. MD simulations demonstrated that curcumin, bisdemethoxycurcumin, and monodemethylcurcumin stabilized p53 mutant R273H, closely mimicking the structural stability of wild-type p53. Pharmacokinetic analysis indicated favorable absorption, distribution, metabolism, and excretion profiles for most derivatives, with low toxicity predicted for the majority.
Curcumin and its derivatives exhibit dual functions as p53 enhancers and reactivators of the p53 mutant R273H. Hexahydrocurcumin and tetrahydrocurcumin emerged as promising compounds with strong bioactivity and favorable pharmacokinetic properties, suggesting their potential as anticancer agents. Further and studies are necessary to validate these findings and explore their therapeutic applications.
p53是一种关键的肿瘤抑制蛋白，负责调控细胞周期并诱导细胞凋亡。该基因的突变，尤其是DNA结合结构域的突变，由于转录活性丧失，常与各种癌症相关。姜黄素及其衍生物已显示出作为p53增强剂和突变型p53重新激活剂的潜力。本研究采用多种方法评估姜黄素衍生物增强野生型p53表达和恢复p53突变体R273H功能的潜力。
从PubChem中选择姜黄素和20种衍生物进行计算分析。使用定量构效关系（QSAR）分析评估它们作为p53增强剂的潜力。进行分子对接以确定它们与野生型和突变型p53蛋白的结合亲和力，随后进行分子动力学（MD）模拟以评估配体-受体稳定性。使用预测计算模型进行药代动力学和毒性评估，以评估它们的类药性质。
QSAR分析确定六氢姜黄素（可能活性[Pa]：0.837）和四氢姜黄素（Pa：0.752）是最有效的p53增强剂。分子对接显示姜黄素衍生物在关键的p53结合残基处具有很强的结合亲和力，特别是通过与R273H突变体的His 273形成氢键。MD模拟表明，姜黄素、双去甲氧基姜黄素和单去甲基姜黄素使p53突变体R273H稳定，紧密模拟野生型p53的结构稳定性。药代动力学分析表明，大多数衍生物具有良好的吸收、分布、代谢和排泄特性，预计大多数衍生物毒性较低。
姜黄素及其衍生物作为p53增强剂和p53突变体R273H的重新激活剂具有双重功能。六氢姜黄素和四氢姜黄素是具有很强生物活性和良好药代动力学性质的有前景的化合物，表明它们作为抗癌剂的潜力。需要进一步的实验和研究来验证这些发现并探索它们的治疗应用。
