Structural analysis of binding functionality of folic acid-PEG dendrimers against folate receptor

• Published in: Journal of molecular graphics & modelling Vol. 72; pp. 201 - 208
• Main Authors: Sampogna-Mireles, Diana, Araya-Durán, Ingrid D., Márquez-Miranda, Valeria, Valencia-Gallegos, Jesús A., González-Nilo, Fernando D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2017
• Subjects: Dendrimer; Dendrimers - chemistry; Drug delivery system; Folate receptor; Folate Receptor 1 - chemistry; Folate Receptor 1 - metabolism; Folic acid; Folic Acid - chemistry; Humans; Hydrogen Bonding; Models, Molecular; Molecular dynamics; PEG; Polyethylene Glycols - chemistry; Solvents - chemistry; Molecular dynamics; Dendrimer; Folate receptor; PEG; Drug delivery system; Folic acid
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2017.01.004

[Display omitted] •This molecular dynamics study validated that PEG750 and PEG3350 did not interfere over folate receptor binding functionality.•Although kinetic binding may be affected, the folate fragment from FA-PEG dendrimers remained exposed to the solvent before approaching to folate receptor, and could selectively direct the dendrimer to FR-α.•FA-PEG3350 dendrimer showed a slightly better interaction with FR-α than FA-PEG750 dendrimer.•Theoretical evidence supports that the proposed PEG-folic acid dendrimers represent a new viable alternative as drug delivery systems for cancer therapies. Dendrimers functionalized with folic acid (FA) are drug delivery systems that can selectively target cancer cells with folate receptors (FR-α) overexpression. Incorporation of polyethylene glycol (PEG) can enhance dendrimers solubility and pharmacokinetics, but ligand-receptor binding must not be affected. In this work we characterized, at atomic level, the binding functionality of conventional site-specific dendrimers conjugated with FA with PEG 750 or PEG 3350 as a linker. After Molecular Dynamics simulation, we observed that both PEG’s did not interfere over ligand-receptor binding functionality. Although binding kinetics could be notably affected, the folate fragment from both dendrimers remained exposed to the solvent before approaching selectively to FR-α. PEG 3350 provided better solubility and protection from enzymatic degradation to the dendrimer than PEG 750. Also, FA-PEG3350 dendrimer showed a slightly better interaction with FR-α than FA-PEG750 dendrimer. Therefore, theoretical evidence supports that both dendrimers are suitable as drug delivery systems for cancer therapies.