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Molecular docking study of various Enterovirus-A71 3C protease proteins and their potential inhibitors
Tran Thao Vy Le1,2, Phuc-Chau Do1,2
1School of Biotechnology, International University, Ho Chi Minh City, Vietnam.
Insights
Hand, foot, and mouth disease (HFMD) has no available therapy. This study evaluated antiviral agents against Enterovirus-A71 3C protease (3Cpro), finding Hesperidin most promising for broad-spectrum inhibition of EV-A71 strains.
Area of Science:
- Virology
- Drug Discovery
- Biochemistry
Background:
- Hand, foot, and mouth disease (HFMD) is a prevalent viral illness in children with no existing vaccines or treatments.
- Current research on EV-A71 3C protease (3Cpro) inhibitors lacks a broad-spectrum approach, hindering effective antiviral development.
- Viral mutations necessitate the evaluation of antiviral agents against diverse strains and mutants.
Purpose of the Study:
- To identify broad-spectrum antiviral agents targeting Enterovirus-A71 3C protease (3Cpro).
- To assess the inhibitory potential of known and novel compounds against various EV-A71 3Cpro strains and mutants.
- To investigate the impact of specific mutations on drug-target interactions.
Main Methods:
- In silico screening of 21 reported inhibitors against eight EV-A71 3Cpro variants (wild-type and mutants).
- Molecular docking of 29 additional candidate compounds to predict binding affinity and spectrum.
- Comparative analysis of inhibitory effects and mutation impact on docking scores.
Main Results:
- Hesperidin demonstrated superior 3Cpro inhibitory capability compared to FIOMC and Rupintrivir.
- FIOMC exhibited a broader anti-3Cpro spectrum than Rupintrivir.
- The E71A mutation significantly affected the docking results of evaluated ligands.
Conclusions:
- Hesperidin is a highly promising candidate for broad-spectrum inhibition of EV-A71 3Cpro.
- Further in vitro studies are warranted to validate Hesperidin's efficacy against EV-A71 3Cpro and compare it with FIOMC.
- Understanding mutation impacts is crucial for developing effective, broad-spectrum antiviral therapies for HFMD.
Abstract:
Hand, foot, and mouth disease (HFMD) is a common infection that primarily affects children in preschool and kindergarten; however, there is yet no vaccination or therapy available. Despite the fact that current research is only focused on numerous strains of Enterovirus-A71 (EV-A71) 3C protease (3Cpro), these investigations are entirely separate and unrelated. Antiviral agents must therefore be tested on several EV strains or mutations. In total, 21 previously reported inhibitors were evaluated for inhibitory effects on eight EV-A71 3Cpro, including wild-type and mutant proteins in this study, and another 29 powerful candidates with inhibitory effects on EV-A71 were investigated using the molecular docking approach. This method is to determine the broad-spectrum of the antiviral agents on a range of strains or mutants because the virus frequently has mutations. Even though Rupintrivir is reported to pass phase I clinical trial, 4-iminooxazolidin-2-one moiety (FIOMC) was shown to have a broader anti-3Cpro spectrum than Rupintrivir. Meanwhile, Hesperidin possessed a better 3Cpro inhibitory capability than FIOMC. Thus, it could be considered the most promising candidate for inhibiting various strains of EV-A71 3Cpro proteins in the newly anti-EV compounds group. Furthermore, the mutation at E71A has the most significant impact on the docking results of all ligands evaluated. Future in vitro experiments on Hesperidin's ability to inhibit 3Cpro activity should be conducted to compare with FIOMC's in vitro results and validate the current in silico work.
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