Conjugated beta-cyclodextrin enhances the affinity of folic acid towards FR alpha: Molecular dynamics study

Al-Thiabat, Mohammad G. and Gazzali, Amirah Mohd and Mohtar, Noratiqah and Murugaiyah, Vikneswaran and Kamarulzaman, Ezatul Ezleen and Yap, Beow Keat and Abd Rahman, Noorsaadah and Othman, Rozana and Wahab, Habibah A. (2021) Conjugated beta-cyclodextrin enhances the affinity of folic acid towards FR alpha: Molecular dynamics study. Molecules, 26 (17). ISSN 1420-3049, DOI

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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.

Item Type: Article
Funders: Universiti Malaya, LRGS NanoMite-Ministry of Higher Education, Malaysia[RU029-2014/5526306], Universiti Malaya, LRGS NanoMite-Ministry of Higher Education, Malaysia[RU029D-2014]
Uncontrolled 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
Subjects: Q Science > QD Chemistry
Divisions: Faculty of Pharmacy
Depositing User: Ms Zaharah Ramly
Date Deposited: 20 Jun 2022 08:10
Last Modified: 20 Jun 2022 08:10

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