title: An induced pocket for the binding of potent fusion inhibitor CL-385319 with H5N1 influenza virus hemagglutinin.
abstract: The influenza glycoprotein hemagglutinin (HA) plays crucial roles in the early stage of virus infection, including receptor binding and membrane fusion. Therefore, HA is a potential target for developing anti-influenza drugs. Recently, we characterized a novel inhibitor of highly pathogenic H5N1 influenza virus, CL-385319, which specifically inhibits HA-mediated viral entry. Studies presented here identified the critical binding residues for CL-385319, which clustered in the stem region of the HA trimer by site-directed mutagenesis. Extensive computational simulations, including molecular docking, molecular dynamics simulations, molecular mechanics generalized Born surface area (MM_GBSA) calculations, charge density and Laplacian calculations, have been carried out to uncover the detailed molecular mechanism that underlies the binding of CL-385319 to H5N1 influenza virus HA. It was found that the recognition and binding of CL-385319 to HA proceeds by a process of "induced fit" whereby the binding pocket is formed during their interaction. Occupation of this pocket by CL-385319 stabilizes the neutral pH structure of hemagglutinin, thus inhibiting the conformational rearrangements required for membrane fusion. This "induced fit" pocket may be a target for structure-based design of more potent influenza fusion inhibitors.
authors.affiliation: School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Runming
authors.initials: R
authors.lastname: Li
authors.forename: Deshou
authors.initials: D
authors.lastname: Song
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Zhu
authors.forename: Hanhong
authors.initials: H
authors.lastname: Xu
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001549:Benzamides; D004355:Drug Stability; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D053124:Influenza A Virus, H5N1 Subtype / Q000737:chemistry* / Q000235:genetics; D008561:Membrane Fusion / Q000187:drug effects; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D055550:Protein Stability; D013329:Structure-Activity Relationship
chemical_list: C560737:3-fluoro-N-(2-(1-piperidinyl)ethyl)-5-(trifluoromethyl)benzamide; D000998:Antiviral Agents; D001549:Benzamides; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006845:Hydrocarbons, Fluorinated; D010880:Piperidines