Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. An In Silico Insight
Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to inter...
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doaj-a08fd84cf58b4731b2bef61e1d9510572021-02-19T00:05:46ZengMDPI AGMolecules1420-30492021-02-01261079107910.3390/molecules26041079Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. An In Silico InsightMohammad G. Al-Thiabat0Fadi G. Saqallah1Amirah Mohd Gazzali2Noratiqah Mohtar3Beow Keat Yap4Yee Siew Choong5Habibah A Wahab6School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, MalaysiaInstitute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Gelugor 11800, Penang, MalaysiaSchool of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor 11800, Penang, MalaysiaFolate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.https://www.mdpi.com/1420-3049/26/4/1079folate receptor alphafolic acid and antifolatesmolecular dockingmolecular dynamicsMM-PBSAH-bonds |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mohammad G. Al-Thiabat Fadi G. Saqallah Amirah Mohd Gazzali Noratiqah Mohtar Beow Keat Yap Yee Siew Choong Habibah A Wahab |
spellingShingle |
Mohammad G. Al-Thiabat Fadi G. Saqallah Amirah Mohd Gazzali Noratiqah Mohtar Beow Keat Yap Yee Siew Choong Habibah A Wahab Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. An In Silico Insight Molecules folate receptor alpha folic acid and antifolates molecular docking molecular dynamics MM-PBSA H-bonds |
author_facet |
Mohammad G. Al-Thiabat Fadi G. Saqallah Amirah Mohd Gazzali Noratiqah Mohtar Beow Keat Yap Yee Siew Choong Habibah A Wahab |
author_sort |
Mohammad G. Al-Thiabat |
title |
Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. An In Silico Insight |
title_short |
Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. An In Silico Insight |
title_full |
Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. An In Silico Insight |
title_fullStr |
Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. An In Silico Insight |
title_full_unstemmed |
Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. An In Silico Insight |
title_sort |
heterocyclic substitutions greatly improve affinity and stability of folic acid towards frα. an in silico insight |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-02-01 |
description |
Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations. |
topic |
folate receptor alpha folic acid and antifolates molecular docking molecular dynamics MM-PBSA H-bonds |
url |
https://www.mdpi.com/1420-3049/26/4/1079 |
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