An effective molecular blocker of ion channel of M2 protein as anti-influenza a drug

Abstract

Design of a drug compound that can effectively bind to the M2 ion channel and block the diffusion of hydrogen ions (H+) through and inhibit influenza A virus replication is an important task. Known anti-influenza drugs amantadine and rimantadine have a weak effect on influenza A virus. A new class of positively charged, +2 e.u., molecules is proposed here to block diffusion of H+ ion through the M2 channel. Several drug candidates, derivatives of a lead compound (diazabicyclooctane), were proposed and investigated. Molecular dynamics of thermal fluctuations of M2 protein structure and ionization-conformation coupling of all the ionizable residues were simulated at physiological pH. The influence of the most probable mutations of key drug-binding amino acid residues in the M2 ion channel were investigated too. It is shown that the suggested new blocker has high binding affinity for the M2 channel. There are two in-channel binding sites of high affinity, the first one has H-bonds with two of four serine residues Ser-31A (B) or Ser-31C(D), and the second one has H-bonds with two of four histidine residues His-37A (B), or His-37C(D). The main advantage of the new drug molecule is the positive charge, +2 e.u., which creates a positive electrostatic potential barrier (in addition to a steric one) for a transfer of H+ ion through M2 channel and may serve as an effective anti-influenza A virus drug. Communicated by Ramaswamy H. Sarma