Conjugated beta-cyclodextrin enhances the affinity of folic acid towards FR alpha: Molecular dynamics study
Document Type
Article
Publication Date
9-1-2021
Abstract
Drug targeting is a progressive area of research with folate receptor alpha (FR alpha) receiving significant attention as a biological marker in cancer drug delivery. The binding affinity of folic acid (FA) to the FR alpha active site provides a basis for recognition of FR alpha. In this study, FA was conjugated to beta-cyclodextrin (beta CD) 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 FR alpha 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-beta CDs created more dynamically stable systems with FR alpha than the apo-FR alpha system. All systems reached equilibrium with stable RMSD values ranging from 1.9-2.4 angstrom and the average residual fluctuation values of the FR alpha backbone atoms for all residues (except for terminal residues ARG8, THR9, THR214, and LEU215) were less than 2.1 angstrom with a consistent Rg value of around 16.8 angstrom throughout the MD simulation time (0-100 ns). The conjugation with beta CD improved the stability and decreased the mobility of all the residues (except residues 149-151) compared to FA-FR alpha and apo-FR alpha 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-FR alpha system, and these residues might have a direct role in increasing the stability of holo systems.
Keywords
Targeted drug delivery system, Folate receptor alpha, Folic acid-conjugated cyclodextrins, Molecular docking, Molecular dynamics, Radius of gyration (Rg), H-bonds, MM-PBSA, MM-PBSA per residue energy decomposition
Divisions
pharmacy
Funders
Universiti Malaya, LRGS NanoMite-Ministry of Higher Education, Malaysia[RU029-2014/5526306],Universiti Malaya, LRGS NanoMite-Ministry of Higher Education, Malaysia[RU029D-2014]
Publication Title
Molecules
Volume
26
Issue
17
Publisher
MDPI
Publisher Location
ST ALBAN-ANLAGE 66, CH-4052 BASEL, SWITZERLAND