TY - JOUR
T1 - Complexation of methotrexate via ligand diffusion molecular dynamic simulations under neutral, basic, and acidic conditions
AU - Bello, Martiniano
AU - Rodríguez-Fonseca, Rolando Alberto
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - Binding free energy
KW - Dendrimer
KW - Drugs
KW - Ligand diffusion molecular dynamics simulations
KW - PAMAM-G4
UR - http://www.scopus.com/inward/record.url?scp=85071527720&partnerID=8YFLogxK
U2 - 10.1016/j.jmgm.2019.107443
DO - 10.1016/j.jmgm.2019.107443
M3 - Artículo
C2 - 31479949
AN - SCOPUS:85071527720
SN - 1093-3263
VL - 93
JO - Journal of Molecular Graphics and Modelling
JF - Journal of Molecular Graphics and Modelling
M1 - 107443
ER -
