Susceptibility of inhibitors against 3C protease of coxsackievirus A16 and enterovirus A71 causing hand, foot and mouth disease: A molecular dynamics study.
Hand foot and mouth disease (HFMD) epidemic has occurred in many countries. Coxsackievirus A16 (CV-A16) and Enterovirus A71 (EV-A71) are the main causes of HFMD. Up to now, there are no anti-HFMD drugs available. Rupintrivir, a broad-spectrum inhibitor, is a drug candidate for HFMD treatment, while other HFMD inhibitors designed from several studies have a relatively low efficiency. Therefore, in this work we aim to study the binding mechanisms of rupintrivir and a peptidic α,β-unsaturated ethyl ester (SG85) against both CV-A16 and EV-A71 3C proteases (3Cpro) using all-atoms molecular dynamics simulation. The obtained results indicate that SG85 shows a stronger binding affinity than rupintrivir against CV-A16. Both inhibitors exhibit a comparable affinity against EV-A71 3Cpro. The molecular information of the binding of the two inhibitors to the proteases will be elucidated. Thus, it is implied that these two compounds may be used as leads for further anti-HFMD drug design and development.
Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Patumwan, Bangkok 10330, Thailand.
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Jetsadawisut
Program in Biotechnology, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Bangkok 10330, Thailand.
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Nutho
Structural and Computational Biology Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Bangkok 10330, Thailand.
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Meeprasert
Structural and Computational Biology Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Bangkok 10330, Thailand; Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Patumwan, Bangkok 10330, Thailand. Electronic address: t.rungrotmongkol@gmail.com.
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Rungrotmongkol
Department of Chemistry, Faculty of Science, Chiang Mai University, 239 Huay Kaew Road, Muang District, Chiang Mai 50200, Thailand.
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Kungwan
Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Patumwan, Bangkok 10330, Thailand; Department of Pharmaceutical Technology and Biopharmaceutics, University of Vienna, Vienna 1090, Austria; Institute of Theoretical Chemistry, University of Vienna, Vienna 1090, Austria.
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Wolschann
Computational Chemistry Unit Cell, Department of Chemistry, Faculty of Science, Chulalongkorn University, 254 Phayathai Road, Patumwan, Bangkok 10330, Thailand. Electronic address: supot.h@chula.ac.th.
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Hannongbua
D000086042:3C Viral Proteases; D003546:Cysteine Endopeptidases; D015195:Drug Design; D004770:Enterovirus / Q000201:enzymology*; D029821:Enterovirus A, Human / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006232:Hand, Foot and Mouth Disease / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives; D011485:Protein Binding; D011760:Pyrrolidinones / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007555:Isoxazoles; D009842:Oligopeptides; D010455:Peptides; D011760:Pyrrolidinones; C000618733:SG85 peptide; D014764:Viral Proteins; D010649:Phenylalanine; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; D014633:Valine; C118874:rupintrivir
Coxsackievirus A16; Cysteine protease; Enterovirus A71; Hand foot and mouth disease; Molecular dynamics simulation