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

Martiniano Bello, Rolando Alberto Rodríguez-Fonseca

Research output: Contribution to journalArticle

Abstract

Methotrexate (MTX), an FDA-approved drug employed in the treatment of several types of cancer and autoimmune diseases, is characterized by its poor solubility. Therefore, new strategies have been implemented such as coupling to nanocarriers to increase its solubility. Previous experimental studies have demonstrated complexation of MTX to polyamidoamine of a generation four (PAMAM-G4) dendrimer with a complex stoichiometry of 19/22:1 under neutral conditions, providing important information that can be used to further elucidate the structural and energetic basis of the molecular binding of MTX and PAMAM-G4. In this study, we performed ligand diffusion molecular dynamic simulations (LDMDSs), using 3 μs combined with the molecular mechanics generalized surface area (MMGBSA) approach employing saturating concentrations of MTX to explore the mechanism through which MTX is complexed by PAMAM-G4 at neutral, basic, and acidic conditions. Our results reproduce the reported complex stoichiometry between MTX and PAMAM-G4 in neutral conditions. Binding free energy values suggest a much slower release in neutral and acidic conditions, consistent with the controlled rate of drug release into the bloodstream and when reaching the acidic environment of tumor tissues. Altogether, the methodology employed and the results may be useful in the evaluation of other drugs of pharmaceutical interest.

Original languageEnglish
Article number107443
JournalJournal of Molecular Graphics and Modelling
Volume93
DOIs
StatePublished - Dec 2019

Fingerprint

Complexation
Methotrexate
Stoichiometry
Molecular dynamics
Solubility
Ligands
molecular dynamics
ligands
Molecular mechanics
drugs
Dendrimers
Computer simulation
Drug products
Free energy
Tumors
stoichiometry
solubility
simulation
Tissue
Pharmaceutical Preparations

Keywords

  • Binding free energy
  • Dendrimer
  • Drugs
  • Ligand diffusion molecular dynamics simulations
  • PAMAM-G4

Cite this

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title = "Complexation of methotrexate via ligand diffusion molecular dynamic simulations under neutral, basic, and acidic conditions",
abstract = "Methotrexate (MTX), an FDA-approved drug employed in the treatment of several types of cancer and autoimmune diseases, is characterized by its poor solubility. Therefore, new strategies have been implemented such as coupling to nanocarriers to increase its solubility. Previous experimental studies have demonstrated complexation of MTX to polyamidoamine of a generation four (PAMAM-G4) dendrimer with a complex stoichiometry of 19/22:1 under neutral conditions, providing important information that can be used to further elucidate the structural and energetic basis of the molecular binding of MTX and PAMAM-G4. In this study, we performed ligand diffusion molecular dynamic simulations (LDMDSs), using 3 μs combined with the molecular mechanics generalized surface area (MMGBSA) approach employing saturating concentrations of MTX to explore the mechanism through which MTX is complexed by PAMAM-G4 at neutral, basic, and acidic conditions. Our results reproduce the reported complex stoichiometry between MTX and PAMAM-G4 in neutral conditions. Binding free energy values suggest a much slower release in neutral and acidic conditions, consistent with the controlled rate of drug release into the bloodstream and when reaching the acidic environment of tumor tissues. Altogether, the methodology employed and the results may be useful in the evaluation of other drugs of pharmaceutical interest.",
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Complexation of methotrexate via ligand diffusion molecular dynamic simulations under neutral, basic, and acidic conditions. / Bello, Martiniano; Rodríguez-Fonseca, Rolando Alberto.

In: Journal of Molecular Graphics and Modelling, Vol. 93, 107443, 12.2019.

Research output: Contribution to journalArticle

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AU - Rodríguez-Fonseca, Rolando Alberto

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