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Updated: Jul 14, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
In silico study of the potential of curcumin and its derivatives for increasing wild-type p53 expression and
Sarah Ika Nainggolan1,2, Rajuddin Rajuddin2, Reno Keumalazia Kamarlis2
1Graduate School of Mathematics and Applied Sciences, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia.
Background And Aim:
p53 is a critical tumor suppressor protein responsible for regulating the cell cycle and inducing apoptosis. Mutations in the p53 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 in silico methods to evaluate the potential of curcumin derivatives to enhance wild-type p53 expression and restore the function of the p53 mutant R273H.
Materials And Methods:
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.
Results:
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.
Conclusion:
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 in vitro and in vivo studies are necessary to validate these findings and explore their therapeutic applications.
Insights
Curcumin derivatives show promise in enhancing wild-type p53 and restoring mutant p53 (R273H) function. Hexahydrocurcumin and tetrahydrocurcumin exhibit strong potential as anticancer agents due to favorable bioactivity and pharmacokinetics.
Area of Science:
- Biochemistry
- Molecular Biology
- Computational Chemistry
Background:
- p53 is a crucial tumor suppressor protein regulating cell cycle and apoptosis.
- Mutations in the p53 gene, especially in the DNA-binding domain, are linked to cancer development.
- Curcumin and its derivatives are investigated for their potential to enhance p53 activity.
Purpose of the Study:
- To evaluate curcumin derivatives as p53 enhancers and reactivators of mutant p53 R273H using in silico methods.
- To assess the binding affinities and stability of curcumin derivatives with wild-type and mutant p53.
- To predict the pharmacokinetic and toxicity profiles of these compounds.
Main Methods:
- Quantitative Structure-Activity Relationship (QSAR) analysis for p53 enhancement potential.
- Molecular docking to determine binding affinities with p53 proteins (wild-type and R273H mutant).
- Molecular dynamics (MD) simulations for ligand-receptor stability and pharmacokinetic/toxicity predictions.
Main Results:
- Hexahydrocurcumin and tetrahydrocurcumin identified as potent p53 enhancers via QSAR.
- Curcumin derivatives showed strong binding to p53, with key interactions at His 273 of the R273H mutant.
- MD simulations indicated that certain derivatives stabilize the p53 R273H mutant, mimicking wild-type p53 structure; favorable pharmacokinetic and low toxicity profiles were predicted.
Conclusions:
- Curcumin derivatives possess dual activity: enhancing wild-type p53 and reactivating the p53 R273H mutant.
- Hexahydrocurcumin and tetrahydrocurcumin are promising candidates for anticancer drug development.
- Further in vitro and in vivo studies are warranted to confirm therapeutic potential.
