title: How amantadine and rimantadine inhibit proton transport in the M2 protein channel.
abstract: To understand how antiviral drugs inhibit the replication of influenza A virus via the M2 ion channel, molecular dynamics simulations have been applied to the six possible protonation states of the M2 ion channel in free form and its complexes with two commercial drugs in a fully hydrated lipid bilayer. Among the six different states of free M2 tetramer, water density was present in the pore of the systems with mono-protonated, di-protonated at adjacent position, tri-protonated and tetra-protonated systems. In the presence of inhibitor, water density in the channel was considerably better reduced by rimantadine than amantadine, agreed well with the experimental IC(50) values. With the preferential position and orientation of the two drugs in all states, two mechanisms of action, where the drug binds to the opening pore and the histidine gate, were clearly explained, i.e., (i) inhibitor was detected to localize slightly closer to the histidine gate and can facilitate the orientation of His37 imidazole rings to lie in the close conformation and (ii) inhibitor acts as a blocker, binding at almost above the opening pore and interacts slightly with the three pore-lining residues, Leu26, Ala30 and Ser31. Here, the inhibitors were found to bind very weakly to the channel due to their allosteric hindrance while theirs side chains were strongly solvated.
authors.affiliation: Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Road, Patumwan, Bangkok 10330, Thailand.
authors.forename: Pathumwadee
authors.initials: P
authors.lastname: Intharathep
authors.forename: Chittima
authors.initials: C
authors.lastname: Laohpongspaisan
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.forename: Arthorn
authors.initials: A
authors.lastname: Loisruangsin
authors.forename: Maturos
authors.initials: M
authors.lastname: Malaisree
authors.forename: Panita
authors.initials: P
authors.lastname: Decha
authors.forename: Ornjira
authors.initials: O
authors.lastname: Aruksakunwong
authors.forename: Krit
authors.initials: K
authors.lastname: Chuenpennit
authors.forename: Nopphorn
authors.initials: N
authors.lastname: Kaiyawet
authors.forename: Pornthep
authors.initials: P
authors.lastname: Sompornpisut
authors.forename: Somsak
authors.initials: S
authors.lastname: Pianwanit
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D000547:Amantadine / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D001665:Binding Sites; D006860:Hydrogen Bonding / Q000187:drug effects; D009980:Influenza A virus / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D011522:Protons; D012299:Rimantadine / Q000494:pharmacology*; D012997:Solvents; D014763:Viral Matrix Proteins / Q000378:metabolism*; D014867:Water; D000086082:Viroporin Proteins
chemical_list: D000547:Amantadine; D000998:Antiviral Agents; D011522:Protons; D012299:Rimantadine; D012997:Solvents; D014763:Viral Matrix Proteins; D014867:Water; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins