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Chem Biol Drug Des. 2013 May 6. doi: 10.1111/cbdd.12156. [Epub ahead of print]
Computational Identification of a New Binding Site in Influenza Virus Hemagglutinin for Membrane Fusion Inhibitors.
Sun L, Tian F, Feng B, Liu Z, Zhang L, Pei J.
Source
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P. R. China.
Abstract
The influenza virus hemagglutinin (HA) is a potential drug target for anti-virus treatment. A variety of membrane fusion inhibitors targeting HA have been discovered, but the binding sites and modes, important for understanding membrane fusion and rational drug design, have not yet been elucidated. In this paper, we investigated the possible HA binding sites for the current membrane-fusion inhibitors. Four possible binding pockets (Pocket A, B, C, and D) at the stalk region of HA were detected and defined by using the CAVITY program. Most of the current membrane-fusion inhibitors were reported to bind to Pocket C by amino acid mutation experiments and molecular modeling simulation. However our binding site prediction suggested that Pocket A is the best ligand-binding site other than Pocket C. By using a specific computational protocol combining molecular docking, three-dimensional QSAR, and receptor mimicking, we further found that Pocket A is the putative binding site for a series of membrane-fusion inhibitors (1-phenyl-cycloalkane carbamides). This is further proven by the anti-viral spectrum of the inhibitors. This protocol for the identification of ligand-binding sites in Influenza HA is also applicable for the analysis of other protein targets with no explicit binding information. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
PMID:
23647909
[PubMed - as supplied by publisher]
Computational Identification of a New Binding Site in Influenza Virus Hemagglutinin for Membrane Fusion Inhibitors.
Sun L, Tian F, Feng B, Liu Z, Zhang L, Pei J.
Source
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, P. R. China.
Abstract
The influenza virus hemagglutinin (HA) is a potential drug target for anti-virus treatment. A variety of membrane fusion inhibitors targeting HA have been discovered, but the binding sites and modes, important for understanding membrane fusion and rational drug design, have not yet been elucidated. In this paper, we investigated the possible HA binding sites for the current membrane-fusion inhibitors. Four possible binding pockets (Pocket A, B, C, and D) at the stalk region of HA were detected and defined by using the CAVITY program. Most of the current membrane-fusion inhibitors were reported to bind to Pocket C by amino acid mutation experiments and molecular modeling simulation. However our binding site prediction suggested that Pocket A is the best ligand-binding site other than Pocket C. By using a specific computational protocol combining molecular docking, three-dimensional QSAR, and receptor mimicking, we further found that Pocket A is the putative binding site for a series of membrane-fusion inhibitors (1-phenyl-cycloalkane carbamides). This is further proven by the anti-viral spectrum of the inhibitors. This protocol for the identification of ligand-binding sites in Influenza HA is also applicable for the analysis of other protein targets with no explicit binding information. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
PMID:
23647909
[PubMed - as supplied by publisher]
