Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study
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 t...
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doaj-02e6aac2213a40c6a540cf25239694ba2021-09-09T13:53:28ZengMDPI AGMolecules1420-30492021-08-01265304530410.3390/molecules26175304Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics StudyMohammad G. Al-Thiabat0Amirah Mohd Gazzali1Noratiqah Mohtar2Vikneswaran Murugaiyah3Ezatul Ezleen Kamarulzaman4Beow Keat Yap5Noorsaadah Abd Rahman6Rozana Othman7Habibah A. Wahab8School of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, MalaysiaDepartment of Chemistry, Faculty of Science, Universiti Malaya, Kuala Lumpur 50603, MalaysiaCenter for Natural Products Research and Drug Discovery (CENAR), Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur 50603, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, George Town 11800, MalaysiaDrug 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.https://www.mdpi.com/1420-3049/26/17/5304targeted drug delivery systemfolate receptor alphafolic acid-conjugated cyclodextrinsmolecular dockingmolecular dynamicsradius of gyration (Rg) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mohammad G. Al-Thiabat Amirah Mohd Gazzali Noratiqah Mohtar Vikneswaran Murugaiyah Ezatul Ezleen Kamarulzaman Beow Keat Yap Noorsaadah Abd Rahman Rozana Othman Habibah A. Wahab |
spellingShingle |
Mohammad G. Al-Thiabat Amirah Mohd Gazzali Noratiqah Mohtar Vikneswaran Murugaiyah Ezatul Ezleen Kamarulzaman Beow Keat Yap Noorsaadah Abd Rahman Rozana Othman Habibah A. Wahab Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study Molecules targeted drug delivery system folate receptor alpha folic acid-conjugated cyclodextrins molecular docking molecular dynamics radius of gyration (Rg) |
author_facet |
Mohammad G. Al-Thiabat Amirah Mohd Gazzali Noratiqah Mohtar Vikneswaran Murugaiyah Ezatul Ezleen Kamarulzaman Beow Keat Yap Noorsaadah Abd Rahman Rozana Othman Habibah A. Wahab |
author_sort |
Mohammad G. Al-Thiabat |
title |
Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study |
title_short |
Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study |
title_full |
Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study |
title_fullStr |
Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study |
title_full_unstemmed |
Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study |
title_sort |
conjugated β-cyclodextrin enhances the affinity of folic acid towards frα: molecular dynamics study |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-08-01 |
description |
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. |
topic |
targeted drug delivery system folate receptor alpha folic acid-conjugated cyclodextrins molecular docking molecular dynamics radius of gyration (Rg) |
url |
https://www.mdpi.com/1420-3049/26/17/5304 |
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