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

Sampogna-Mireles, Diana; Araya-Durán, Ingrid; Márquez-Miranda, Valeria; Valencia-Gallegos, Jesús A.; González‐Nilo, Fernando

doi:10.1016/j.jmgm.2017.01.004

Cited by 11 publications

(15 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…H-bonds are essential for protein folding and protein-ligand interactions [32,33]. It is well known that ASP81 is the key residue in the FRα binding site, playing a critical role in increasing ligand binding affinity and anchoring the FA pteridine region deep within the site [27,30,34]. Specifically, the crystal structure used in this study demonstrated that ASP81 formed strong H-bonds with N1 and N2 atoms in the pteridine ring of FA.…”

Section: Hydrogen Bond (H-bond) Propertiesmentioning

confidence: 67%

Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

et al. 2021

View full text Add to dashboard Cite

Drug targeting is a progressive area of research with folate receptor alpha (FRα) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FRα active site provides a basis for recognition of FRα. In this study, FA was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis (molecular docking and molecular dynamics (MD) simulation (100 ns)) to investigate the affinity and stability for the conjugated system compared to unconjugated and apo systems (ligand free). Docking studies revealed that the conjugated FA bound into the active site of FRα with a docking score (free binding energy < −15 kcal/mol), with a similar binding pose to that of unconjugated FA. Subsequent analyses from molecular dynamics (MD) simulations, root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (Rg) demonstrated that FA and FA–βCDs created more dynamically stable systems with FRα than the apo-FRα system. All systems reached equilibrium with stable RMSD values ranging from 1.9–2.4 Å and the average residual fluctuation values of the FRα backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 Å with a consistent Rg value of around 16.8 Å throughout the MD simulation time (0–100 ns). The conjugation with βCD improved the stability and decreased the mobility of all the residues (except residues 149–151) compared to FA–FRα and apo-FRα systems. Further analysis of H-bonds, binding free energy (MM-PBSA), and per residue decomposition energy revealed that besides APS81, residues HIS20, TRP102, HIS135, TRP138, TRP140, and TRP171 were shown to have more favourable energy contributions in the holo systems than in the apo-FRα system, and these residues might have a direct role in increasing the stability of holo systems.

show abstract

Section: Hydrogen Bond (H-bond) Propertiesmentioning

confidence: 67%

Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Overall, the conformation of PEG and its effect on the internal structure of dendrimer were mainly studied until early 2010s, while the effect of PEGylation on the binding affinity to proteins and drug release efficiency have been more focused for the past five years. (Figure 8) [186], which should be highlighted because their simulations captured the effect of PEG on the binding affinity to the receptor protein. Hsu et al simulated PEGylated dendron micelle and serum albumin, showing that the penetration of serum albumin into the micelle core can be suppressed by PEGylation [187].…”

Section: Dendrimersmentioning

confidence: 99%

“…Lim et al [ 184 ] and Barraza et al [ 185 ] respectively simulated paclitaxel and methotrexate drugs interacting PEGylated dendrimers, showing that PEG–PEG crowding decreases the extent of drug release, which helps determine the size and density of PEG for optimal drug release. Sampogna-Mireles et al simulated dendrimers grafted with PEG and folic acid, showing that PEG chains do not reduce the binding affinity between folic acid and folate receptor ( Figure 8 ) [ 186 ], which should be highlighted because their simulations captured the effect of PEG on the binding affinity to the receptor protein. Hsu et al simulated PEGylated dendron micelle and serum albumin, showing that the penetration of serum albumin into the micelle core can be suppressed by PEGylation [ 187 ].…”

Section: Pegylated Nanoparticlesmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

Lee

2020

Pharmaceutics

View full text Add to dashboard Cite

Since the first polyethylene glycol (PEG)ylated protein was approved by the FDA in 1990, PEGylation has been successfully applied to develop drug delivery systems through experiments, but these experimental results are not always easy to interpret at the atomic level because of the limited resolution of experimental techniques. To determine the optimal size, structure, and density of PEG for drug delivery, the structure and dynamics of PEGylated drug carriers need to be understood close to the atomic scale, as can be done using molecular dynamics simulations, assuming that these simulations can be validated by successful comparisons to experiments. Starting with the development of all-atom and coarse-grained PEG models in 1990s, PEGylated drug carriers have been widely simulated. In particular, recent advances in computer performance and simulation methodologies have allowed for molecular simulations of large complexes of PEGylated drug carriers interacting with other molecules such as anticancer drugs, plasma proteins, membranes, and receptors, which makes it possible to interpret experimental observations at a nearly atomistic resolution, as well as help in the rational design of drug delivery systems for applications in nanomedicine. Here, simulation studies on the following PEGylated drug topics will be reviewed: proteins and peptides, liposomes, and nanoparticles such as dendrimers and carbon nanotubes.

show abstract

“…They built PEGylated telodendrimers using structure based design, virtual screening, docking and MD simulations, being the first group to use these techniques to rationally design nanocarriers for drug delivery purposes. Sampogna‐Mireles and co‐workers, performed atomistic MD simulations on PEGylated dendrimers functionalized with folic acid to selectively target cancer cells that present an overexpression of folate receptors. Their experiments showed that PEGylation did not interfere in ligand‐receptor binding leading to another viable drug delivery method.…”

Section: Pegylation Of Nanocarriersmentioning

confidence: 99%

Analyzing PEGylation through Molecular Dynamics Simulations

et al. 2018

View full text Add to dashboard Cite

Poly(ethylene) glycol (PEG) is the most used polymer in drug delivery due to its unique properties, such as reduced toxicity and high solubility. PEGylation is the process of attaching PEG chains to compounds. Its effect on drug delivery has motivated a lot of experimental and computational studies. To explain and complement experimental findings, all-atom, coarsegrained and multi-scale molecular dynamics simulations are being increasingly done. This review summarizes the computational studies using molecular dynamics that have been done regarding PEG and PEGylation of small molecules, proteins, peptides and drug nanocarriers such as micelles, liposomes, dendrimers and carbon nanotubes. Generally, the various studies presented indicate that molecular dynamics simulations can be a powerful tool in explaining and predicting experimental results and are efficient in providing an atomic-level insight into the interactions between PEG molecules and other compounds. In particular, MD simulations are nowadays routinely used to provide direct insight into the dominant conformations formed, range of interactions established, and effect of PEGylation on the structural and dynamic properties of different drugs or therapeutic agents, enabling an atomic level analysis of a variety aspects including ionic concentration, identify of ions present, and specific PEG size and number of molecules. Figure 1. Types of PEG chains. X represents functional groups and n represents the number of individual units in the chain. In multi-arm PEG chains oxygen atoms were omitted for clarity.

show abstract

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

Cited by 11 publications

References 50 publications

Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

Analyzing PEGylation through Molecular Dynamics Simulations

Contact Info

Product

Resources

About