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Preceding experimental findings revealed that the release of indomethacin decreased when a folate conjugate G4-PAMAM (folate-G4-PAMAM) dendrimer was used compared with its unconjugated dendrimer (G4-PAMAM). Further, better encapsulation of the conjugated dendrimer was achieved, information useful for elucidating the structural and energetic basis of indomethacin on folate-G4-PAMAM encapsulation. In this study, we employed a ligand diffusion molecular dynamic simulations (LDMDSs) strategy combined with the molecular mechanics-generalized-born surface area (MMGBSA) approach to explore the mechanism by which indomethacin conjugated to folate-G4-PAMAM dendrimer forms complexes better than G4-PAMAM dendrimer. To this, we first constructed and equilibrated the folate-G4-PAMAM dendrimer, then, this system was submitted to docking and molecular dynamics (MD) simulation to evaluate its ability to form a stable complex with the folate receptor (FR). We observed that the folate-G4-PAMAM dendrimer was able to bind FR with higher affinity than free folic acid. Based on these results, we further performed LDMDSs to assess folate-G4-PAMAM dendrimer and G4-PAMAM dendrimer contacts with indomethacin. Our results correlate with experimental data, which confirm that folate-G4-PAMAM dendrimers are capable of most rapidly binding greater numbers of indomethacin molecules than G4-PAMAM, which suggests better loading and slower release occurs when the functionalized G4-PAMAM dendrimer is used. The simulations further revealed that van der Waals interactions govern the affinity. Communicated by Ramaswamy H. Sarma

Binding of Folate-G4-PAMAM dendrimer conjugate with indomethacin via ligand diffusion MD simulations