Molecular dynamics simulations of PPI dendrimer–drug complexes

Abstract

Dendrimeric nanoparticles are potential drug delivery devices which can enhance the solubility of hydrophobic drugs, thus increasing their bioavailability and sustained release action. A quantitative understanding of the dendrimer–drug interactions can give valuable insight into the solubility and release profile of hydrophobic drug molecules in various solvent conditions. Fully atomistic molecular dynamics (MD) simulations have been performed to study the interactions of G5 PPI^EDA (G5 ethylenediamine cored poly(propylene imine)) dendrimer and two well known drugs (Famotidine and Indomethacin) at different pH conditions. The study suggested that at low pH the dendrimer–drug complexes are thermodynamically unstable as compared to neutral and high pH conditions. Calculated Potential of Mean Force (PMF) by umbrella sampling showed that the release of drugs from the dendrimer at low pH is spontaneous, median release at neutral pH and slow release at high pH. In addition, Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) binding free energy calculations were also performed at each umbrella sampling window to identify the various energy contributions. To understand the effect of dendrimer chemistry and topology on the solubility and release profile of drugs, this study is extended to explore the solubility and release profile of phenylbutazone drug complexed with G3 poly(amidoamine) and G4 diaminobutane cored PPI dendrimers. The results indicate that the pH-induced conformational changes in dendrimer, ionization states, dendrimer type and pK_a of the guest molecules influence the free energy barrier and stability of complexation, and thus regulate drug loading, solubility and release.