Folic Acid and Leucovorin Have Potential to Prevent SARS-CoV-2-Virus Internalization by Interacting with S-Glycoprotein/Neuropilin-1 Receptor Complex

The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identifi...

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Published inMolecules (Basel, Switzerland) Vol. 28; no. 5; p. 2294
Main Authors Škrbić, Ranko, Travar, Maja, Stojiljković, Miloš P., Djuric, Dragan M., Suručić, Relja
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 01.03.2023
MDPI
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ISSN1420-3049
1420-3049
DOI10.3390/molecules28052294

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Abstract The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus’ entry into host cells.
AbstractList The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus' entry into host cells.The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus' entry into host cells.
The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus’ entry into host cells.
The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC 75 value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus’ entry into host cells.
The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC[sub.75] value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus’ entry into host cells.
The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection. Neuropilin-1 (NRP-1) is another host factor involved in virus internalization. The interaction between S-glycoprotein and NRP-1 has been identified as a potential COVID-19 treatment target. Herein, the effectiveness of folic acid and leucovorin in preventing contact between S-glycoprotein and NRP-1 receptors was investigated using in silico studies and then confirmed in vitro. The results of a molecular docking study showed that leucovorin and folic acid had lower binding energies than EG01377, a well-known NRP-1 inhibitor, and lopinavir. Two hydrogen bonds with Asp 320 and Asn 300 residues stabilized the leucovorin, while interactions with Gly 318, Thr 349, and Tyr 353 residues stabilized the folic acid. The molecular dynamic simulation revealed that the folic acid and leucovorin created very stable complexes with the NRP-1. The in vitro studies showed that the leucovorin was the most active inhibitor of the S1-glycoprotein/NRP-1 complex formation, with an IC value of 185.95 µg/mL. The results of this study suggest that folic acid and leucovorin could be considered as potential inhibitors of the S-glycoprotein/NRP-1 complex and, thus, could prevent the SARS-CoV-2 virus' entry into host cells.
Audience Academic
Author Suručić, Relja
Stojiljković, Miloš P.
Škrbić, Ranko
Djuric, Dragan M.
Travar, Maja
AuthorAffiliation 2 Centre for Biomedical Research, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, The Republic of Srpska, Bosnia and Herzegovina
4 Institute of Medical Physiology “Richard Burian”, Faculty of Medicine, University of Belgrade, Višegradska 26/2, 11000 Belgrade, Serbia
5 Department of Pharmacognosy, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, The Republic of Srpska, Bosnia and Herzegovina
3 Department of Microbiology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, The Republic of Srpska, Bosnia and Herzegovina
1 Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Banja Luka, 78000 Banja Luka, The Republic of Srpska, Bosnia and Herzegovina
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Issue 5
Keywords COVID-19
SARS-CoV-2
in vitro
neuropilin-1
in silico
folic acid
leucovorin
Language English
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Snippet The interaction of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain with the host-cell ACE2 receptor is a well-known step in virus infection....
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StartPage 2294
SubjectTerms Amino acids
Angiogenesis
Antiretroviral drugs
Antiviral agents
Blood vessels
Cell receptors
Coronaviruses
COVID-19
COVID-19 Drug Treatment
Flexibility
Folic acid
Folic Acid - metabolism
Glycoproteins
Glycoproteins - metabolism
Health aspects
Humans
in silico
in vitro
Infections
Leucovorin
Ligands
Molecular Docking Simulation
Nervous system
neuropilin-1
Neuropilin-1 - metabolism
Permeability
Pharmaceutical research
Protein Binding
Proteins
RNA polymerase
SARS-CoV-2 - metabolism
Severe acute respiratory syndrome coronavirus 2
Simulation
Testing
Vascular endothelial growth factor
Viral infections
Virus Internalization
Vitamin B
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Title Folic Acid and Leucovorin Have Potential to Prevent SARS-CoV-2-Virus Internalization by Interacting with S-Glycoprotein/Neuropilin-1 Receptor Complex
URI https://www.ncbi.nlm.nih.gov/pubmed/36903540
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Volume 28
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