Molecular Docking of Amino Acid Analogues of Rimantidine

Abstract

M2 channel is a 97-residue single-pass membrane protein with its N-and C-termini directed toward the outside and inside of the virion, re-spectively; it is a homotetramer in its native state. The four TM helicesform a channel in which His37 is the pH sensor and Trp41, the gate. Theadamantane-based drugs, amantadine and rimantadine, which target theM2 channel, have been used as rst-choice antiviral drugs against commu-nity outbreaks of inuenza A viruses for many years, but resistance to theadamantanes has recently become widespread. To overcome this dierentanalogues of rimantidine have been synthesized. The aim of this study isto predict the biological activity of amino acid analogues of rimantidinewith a help of docking studies in order to synthesize only promising can-didates. Twenty analogues of rimantidine with natural amino acids wereused. Docking was performed with the M2 channel as it is very impor-tant in the replicative cycle of inuenza A virus. Crystal structure of thechannel was obtained from RCSB (PDB id: 2rlf). Docking was performedwith GOLD 5.2 using GoldScore tness function. The complexes of riman-tidine analogues with M2 channel were analyzed and their total energieswere calculated in Molegro Molecular Viewer. Total energy of the com-plex rimantidine/M2 channel is -29.437 kJ/mole. All complexes of aminoacid analogues of rimantidine with the channel have lower energies, butthe lowest are the energies of the complexes of Asn-Rim/M2 channel andHis-Rim/M2 channel with -72.475 and -76.440 kJ/mole, respectively. Fromthe energetically point of view complexes will be more stables. This meansthat all rimantidine analogues will block the M2 channel thus will aectthe viral replication cycle. Docking studies are an useful tool for predictionof biological eect of dierent type of compounds and could be applied inshortening the drug design process.