title: Computational and experimental analysis of drug binding to the Influenza M2 channel.
abstract: The Influenza Matrix 2 (M2) protein is the target of Amantadine and Rimantadine which block its H(+) channel activity. However, the potential of these aminoadamantyls to serve as anti-flu agents is marred by the rapid resistance that the virus develops against them. Herein, using a cell based assay that we developed, we identify two new aminoadamantyl derivatives that show increased activity against otherwise resistant M2 variants. In order to understand the distinguishing binding patterns of the different blockers, we computed the potential of mean force of the drug binding process. The results reveal that the new derivatives are less mobile and bind to a larger pocket in the channel. Finally, such analyses may prove useful in designing new, more effective M2 blockers as a means of curbing influenza. This article is part of a Special Issue entitled: Viral Membrane Proteins - Channels for Cellular Networking.
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmund J. Safra Campus, Jerusalem 91904, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Alhadeff
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmund J. Safra Campus, Jerusalem 91904, Israel.
authors.forename: Dror
authors.initials: D
authors.lastname: Assa
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmund J. Safra Campus, Jerusalem 91904, Israel.
authors.forename: Peleg
authors.initials: P
authors.lastname: Astrahan
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmund J. Safra Campus, Jerusalem 91904, Israel.
authors.forename: Miriam
authors.initials: M
authors.lastname: Krugliak
authors.affiliation: Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Edmund J. Safra Campus, Jerusalem 91904, Israel. Electronic address: arkin@huji.ac.il.
authors.forename: Isaiah T
authors.initials: IT
authors.lastname: Arkin
mesh_terms: D000998:Antiviral Agents / Q000378:metabolism* / Q000494:pharmacology; D024882:Drug Resistance, Viral; D056004:Molecular Dynamics Simulation; D014763:Viral Matrix Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000086082:Viroporin Proteins
chemical_list: D000998:Antiviral Agents; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins
keywords: Anti-flu agent; Cell based assay; Channel blocker; Potential of mean force