Complexation of methotrexate via ligand diffusion molecular dynamic simulations under neutral, basic, and acidic...

Area of Science:

• Nanomedicine
• Computational Chemistry
• Drug Delivery

Background:

• Methotrexate (MTX) is an FDA-approved drug for cancer and autoimmune diseases, but suffers from poor solubility.
• Nanocarrier systems, like polyamidoamine (PAMAM-G4) dendrimers, are explored to enhance MTX solubility and delivery.
• Previous studies established MTX-PAMAM-G4 complexation stoichiometry under neutral conditions.

Purpose of the Study:

• To computationally explore the mechanism of MTX complexation by PAMAM-G4 dendrimers.
• To investigate MTX-PAMAM-G4 binding under neutral, basic, and acidic conditions using molecular dynamics.
• To elucidate the structural and energetic basis of MTX-PAMAM-G4 molecular binding.

Main Methods:

• Ligand diffusion molecular dynamic simulations (LDMDSs) were performed for 3 μs.
• Molecular mechanics generalized surface area (MMGBSA) approach was employed.
• Saturating concentrations of MTX were used to study complexation at varying pH.

Main Results:

• The simulations reproduced the experimentally reported MTX-PAMAM-G4 complex stoichiometry under neutral conditions.
• Binding free energy calculations indicated significantly slower MTX release in neutral and acidic environments.
• The findings are consistent with controlled drug release in the bloodstream and tumor tissues.

Conclusions:

• The computational methodology provides insights into MTX-PAMAM-G4 interactions across different pH values.
• The observed binding stability suggests potential for controlled MTX release in therapeutic applications.
• The approach may be valuable for evaluating other drug-dendrimer interactions for pharmaceutical development.