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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434473/ https://www.ncbi.nlm.nih.gov/pubmed/34500740 http://dx.doi.org/10.3390/molecules26175304 |
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author | Al-Thiabat, Mohammad G. Gazzali, Amirah Mohd Mohtar, Noratiqah Murugaiyah, Vikneswaran Kamarulzaman, Ezatul Ezleen Yap, Beow Keat Rahman, Noorsaadah Abd Othman, Rozana Wahab, Habibah A. |
author_facet | Al-Thiabat, Mohammad G. Gazzali, Amirah Mohd Mohtar, Noratiqah Murugaiyah, Vikneswaran Kamarulzaman, Ezatul Ezleen Yap, Beow Keat Rahman, Noorsaadah Abd Othman, Rozana Wahab, Habibah A. |
author_sort | Al-Thiabat, Mohammad G. |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-8434473 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84344732021-09-12 Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study Al-Thiabat, Mohammad G. Gazzali, Amirah Mohd Mohtar, Noratiqah Murugaiyah, Vikneswaran Kamarulzaman, Ezatul Ezleen Yap, Beow Keat Rahman, Noorsaadah Abd Othman, Rozana Wahab, Habibah A. Molecules Article 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. MDPI 2021-08-31 /pmc/articles/PMC8434473/ /pubmed/34500740 http://dx.doi.org/10.3390/molecules26175304 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Al-Thiabat, Mohammad G. Gazzali, Amirah Mohd Mohtar, Noratiqah Murugaiyah, Vikneswaran Kamarulzaman, Ezatul Ezleen Yap, Beow Keat Rahman, Noorsaadah Abd Othman, Rozana Wahab, Habibah A. Conjugated β-Cyclodextrin Enhances the Affinity of Folic Acid towards FRα: Molecular Dynamics Study |
title | 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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434473/ https://www.ncbi.nlm.nih.gov/pubmed/34500740 http://dx.doi.org/10.3390/molecules26175304 |
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