In silico study of the potential of curcumin and its derivatives for increasing wild-type p53 expression and improving the function of p53 mutant R273H

TL;DR

This study uses computer simulations to find curcumin derivatives that can boost wild-type p53 activity and restore function in a cancer-linked p53 mutant.

Contribution

The novel contribution is identifying curcumin derivatives as dual p53 enhancers and reactivators using in silico methods.

Findings

Hexahydrocurcumin and tetrahydrocurcumin showed the highest potential as p53 enhancers based on QSAR analysis.

Curcumin derivatives stabilized the R273H p53 mutant through strong binding and hydrogen bonds.

Most derivatives had favorable pharmacokinetic profiles and low toxicity predictions.

Abstract

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.

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 in vitro and in vivo studies are necessary to validate these findings and explore their therapeutic applications.

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