TY - JOUR

T1 - Design of an Efficient Inhibitor for the Influenza A Virus M2 Ion Channel

AU - Vorobjev, Yu N.

N1 - Publisher Copyright: © 2020, Pleiades Publishing, Inc.

PY - 2020/3/1

Y1 - 2020/3/1

N2 - Influenza A virus is capable of rapidly infecting large human populations, warranting the development of novel drugs to efficiently inhibit virus replication. A transmembrane ion channel formed by the M2 protein plays an important role in influenza virus replication. A reasonable approach to designing an effective antivirus drug is constructing a molecule that binds in the M2 transmembrane proton channel, blocks H+ proton diffusion through the channel, and thus the influenza A virus cycle. The known anti-influenza drugs amantadine and rimantadine have a weak effect on influenza A virus replication. A new class of positively charged molecules, diazabicyclooctane derivatives with a constant charge of +2, was proposed to block proton diffusion through the M2 ion channel. Molecular dynamics simulations were performed to study the temperature fluctuations in the M2 structure, and ionization states of histidine residues were established at physiological pH values. Two types of diazabicyclooctane derivatives were analyzed for binding with the M2 ion channel. An optimal structure was determined for a blocker to most efficiently bind with the M2 ion channel and block proton diffusion. The new molecule is advantageous over amantadine and rimantadine in having a positive charge of +2, which creates a positive electrostatic potential barrier to proton transport through the M2 ion channel in addition to a steric barrier.

AB - Influenza A virus is capable of rapidly infecting large human populations, warranting the development of novel drugs to efficiently inhibit virus replication. A transmembrane ion channel formed by the M2 protein plays an important role in influenza virus replication. A reasonable approach to designing an effective antivirus drug is constructing a molecule that binds in the M2 transmembrane proton channel, blocks H+ proton diffusion through the channel, and thus the influenza A virus cycle. The known anti-influenza drugs amantadine and rimantadine have a weak effect on influenza A virus replication. A new class of positively charged molecules, diazabicyclooctane derivatives with a constant charge of +2, was proposed to block proton diffusion through the M2 ion channel. Molecular dynamics simulations were performed to study the temperature fluctuations in the M2 structure, and ionization states of histidine residues were established at physiological pH values. Two types of diazabicyclooctane derivatives were analyzed for binding with the M2 ion channel. An optimal structure was determined for a blocker to most efficiently bind with the M2 ion channel and block proton diffusion. The new molecule is advantageous over amantadine and rimantadine in having a positive charge of +2, which creates a positive electrostatic potential barrier to proton transport through the M2 ion channel in addition to a steric barrier.

KW - diazabicyclooctane derivatives

KW - influenza A virus

KW - inhibitors

KW - ion channel

KW - ionization of histidine residues

KW - M2 protein

KW - molecular dynamics

UR - http://www.scopus.com/inward/record.url?scp=85084143359&partnerID=8YFLogxK

UR - https://www.elibrary.ru/item.asp?id=43288600

U2 - 10.1134/S0026893320020168

DO - 10.1134/S0026893320020168

M3 - Article

AN - SCOPUS:85084143359

VL - 54

SP - 281

EP - 291

JO - Molecular Biology

JF - Molecular Biology

SN - 0026-8933

IS - 2

ER -