ABSTRACT
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,ß-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.
Subject(s)
Enterovirus A, Human/enzymology , Enterovirus/enzymology , Molecular Dynamics Simulation , Viral Proteins/antagonists & inhibitors , 3C Viral Proteases , Cysteine Endopeptidases , Drug Design , Enzyme Inhibitors/pharmacology , Hand, Foot and Mouth Disease/virology , Humans , In Vitro Techniques , Isoxazoles/pharmacology , Oligopeptides/pharmacology , Peptides/pharmacology , Phenylalanine/analogs & derivatives , Protein Binding , Pyrrolidinones/pharmacology , Valine/analogs & derivativesSubject(s)
Drug Resistance, Viral , Influenza A Virus, H5N1 Subtype/enzymology , Influenza A Virus, H5N1 Subtype/physiology , Neuraminidase/antagonists & inhibitors , Neuraminidase/metabolism , Oseltamivir/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Influenza A Virus, H5N1 Subtype/drug effects , Models, Molecular , Molecular Conformation , Mutation , Neuraminidase/chemistry , Neuraminidase/genetics , Oseltamivir/chemistry , Oseltamivir/metabolismABSTRACT
Recently, Guo et al. have reported structural as well as the binding energy data of the particular interactions between the cleavage sites of hemagglutinin and serine proteases, trypsin and furin, using molecular docking approach. Due to a wrong assignment of protonation state on the histidine, one of the catalytic triad in the active site of both enzymes, their docking results are contradictory with the fundamental principle and previous theoretical studies of the known cleavage mechanism in serine proteases.
