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Objectives <p>The study aims to investigate the potential of digoxin as an inhibitor of PD-1 through an integrated approach involving in silico methods, NMR NOESY, and in vitro evaluations (MTT assay), followed by the formulation and evaluation of digoxin-loaded glycerosomes for the treatment of skin cancer.</p> Methods <p>Initially, we performed molecular docking to determine the binding energy and interaction profile of digoxin with PD-1. Then, NOESY analysis confirmed molecular interactions and hydrogen bonding between digoxin and the target protein. Furthermore, to estimate the cytotoxicity of digoxin, an MTT assay was carried out, resulting in an IC₅₀ value of 2 µM against skin cancer cells (A431). Based on these findings, digoxin-loaded glycerosomes were prepared using the thin film hydration method and optimized with the Box-Behnken Design (BBD). The formulation was assessed for entrapment efficiency (%), in vitro penetration (%), particle size, zeta potential, TEM analysis, stability, and skin penetration using confocal microscopy.</p> Results <p>The molecular docking analysis revealed a binding affinity of -7.6 kcal/mol, suggesting a significant interaction between digoxin and PD-1. In NOESY analysis, downfield shifts (0-3 ppm), deshielding of protons, and broadening of peaks indicate that interactions are occurring between the ligand and the protein. The MTT assay revealed significant cytotoxicity with an IC₅₀ of 2 µM. The optimized digoxin-loaded glycerosomes have displayed an entrapment efficiency of 92.93± 2.15%, an in vitro penetration of 85.026± 1.12 %, a particle size of 228.1± 1.27 nm, and a zeta potential of -26.9 mV, highlighting their potential for enhanced skin permeation and drug delivery.</p> Conclusion <p>The step-by-step process from computational evaluation to laboratory testing confirmed digoxin’s interaction with PD-1 and cytotoxicity, highlighting its potential to serve as a PD-1 inhibitor. The digoxin-loaded glycerosomes, optimized using the Box–Behnken design, demonstrated enhanced drug entrapment, release, stability, and skin penetration. This makes them a promising transdermal drug delivery system for treating skin cancer.</p>

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Digoxin as a PD-1 Inhibitor: In Silico Analysis, NMR Characterization, Cytotoxicity Evaluation, and Glycerosome-Mediated Delivery for Enhanced Skin Cancer Therapy

  • 期刊论文

  • 发表日期：

    2026年1月29日

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  • Neha Sharma,
  • Rupa Mazumder,
  • Pallavi Rai,
  • Abhijit Debnath

摘要

Objectives

The study aims to investigate the potential of digoxin as an inhibitor of PD-1 through an integrated approach involving in silico methods, NMR NOESY, and in vitro evaluations (MTT assay), followed by the formulation and evaluation of digoxin-loaded glycerosomes for the treatment of skin cancer.

Methods

Initially, we performed molecular docking to determine the binding energy and interaction profile of digoxin with PD-1. Then, NOESY analysis confirmed molecular interactions and hydrogen bonding between digoxin and the target protein. Furthermore, to estimate the cytotoxicity of digoxin, an MTT assay was carried out, resulting in an IC₅₀ value of 2 µM against skin cancer cells (A431). Based on these findings, digoxin-loaded glycerosomes were prepared using the thin film hydration method and optimized with the Box-Behnken Design (BBD). The formulation was assessed for entrapment efficiency (%), in vitro penetration (%), particle size, zeta potential, TEM analysis, stability, and skin penetration using confocal microscopy.

Results

The molecular docking analysis revealed a binding affinity of -7.6 kcal/mol, suggesting a significant interaction between digoxin and PD-1. In NOESY analysis, downfield shifts (0-3 ppm), deshielding of protons, and broadening of peaks indicate that interactions are occurring between the ligand and the protein. The MTT assay revealed significant cytotoxicity with an IC₅₀ of 2 µM. The optimized digoxin-loaded glycerosomes have displayed an entrapment efficiency of 92.93± 2.15%, an in vitro penetration of 85.026± 1.12 %, a particle size of 228.1± 1.27 nm, and a zeta potential of -26.9 mV, highlighting their potential for enhanced skin permeation and drug delivery.

Conclusion

The step-by-step process from computational evaluation to laboratory testing confirmed digoxin’s interaction with PD-1 and cytotoxicity, highlighting its potential to serve as a PD-1 inhibitor. The digoxin-loaded glycerosomes, optimized using the Box–Behnken design, demonstrated enhanced drug entrapment, release, stability, and skin penetration. This makes them a promising transdermal drug delivery system for treating skin cancer.