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

Abstract

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.

Potential <i>Adenostemma lavenia</i> and <i>Muntingia calabura</i> Extracts to Inhibit Cyclooxygenase-2 Activity as a Therapeutic Strategy for Anti-inflammation: Experimental and Theoretical Studies

“…H-bonds are critical for protein folding and proteinligand interactions [50]. These results are consistent with the docking analysis that the ligand 1a,9b-dihydro-1H-cyclopropa[a]anthracene does not form hydrogen interactions with COX-2 but forms hydrophobic interactions to stabilize the complex structure formed.…”

Naturally Occurring 8ß,13ß-kaur-15-en-17-al and Anti-Malarial Activity from Podocarpus polystachyus Leaves

“…Reconstruction of missing atoms and assignment of atomic charges and radii using the SWANSON force field (AMBER ff99 charges with optimized radii) was performed [ 46 ]. Protonation at pH 7.40 was carried out using (PROPKA3) [ 47 , 48 ]. The MolProbity web service was accessed on 14 March 2022 ( ) for correction of bad contacts, the addition of missing hydrogen atoms, flipping of HIS, GLU, and ASN residues [ 48 , 49 ].…”

“…Protonation at pH 7.40 was carried out using (PROPKA3) [ 47 , 48 ]. The MolProbity web service was accessed on 14 March 2022 ( ) for correction of bad contacts, the addition of missing hydrogen atoms, flipping of HIS, GLU, and ASN residues [ 48 , 49 ].…”

“…The best-docked conformation pose of the selected compounds ( 1 and 2 ) in the Pf LDH binding site was chosen as the starting structure to run the molecular dynamic (MD) simulations (100 ns). Using AMBER 18 (University of California San Francisco, CA, USA) [ 54 ], the MD simulations were performed based on the methods previously described [ 48 , 50 ]. Briefly, the general AMBER force field (GAFF) and the AMBER ff14SB force field were applied, respectively, on the ligands and Pf LDH.…”

Molecular Dynamics Simulations: Advances and Applications

“…The tested compounds inhibiting HpG6PD represent promising novel drug candidates against H. pylori . Al-Thiabat et al addressed drugs targeting folate receptor alpha (FRα), a biological marker in cancer drug delivery [ 3 ]. Folic acid (FA) was conjugated to beta-cyclodextrin (βCD) and subjected to in silico analysis by molecular docking and MD simulations to investigate the affinity and stability of the conjugated system compared to unconjugated and apo systems (ligand-free).…”