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Editor, Senior Moderator
Selective Binding of Antiinfluenza Drugs and Their Analogues to ?Open? and ?Closed? Conformations of H5N1 Neuraminidase
Pei Wang? and John Z. H. Zhang*???
Institute of Theoretical and Computational Science, and State Key Laboratory of Precision Spectroscopy, Department of Physics, East China Normal University, Shanghai 200062, China, and Department of Chemistry, New York University, New York, New York 10003
J. Phys. Chem. B, Article ASAP
DOI: 10.1021/jp1030224
Publication Date (Web): September 22, 2010
Copyright ? 2010 American Chemical Society
It was suggested that the open conformation of the 150-loop of H5N1 avian influenza neuraminidase is intrinsically lower in energy than the closed conformation and that oseltamivir (tamiflu) favors binding to the closed conformation through a relatively slow conformational change [Russell, R. J. Nature2006, 443, 45−49]. In the present work, a systematic computational study is performed to investigate the binding mechanism of five ligands to H5N1 neuraminidase (H5N1 NA) with the 150-loop in both open and closed conformations through molecular docking, molecular dynamics simulations, and MM/PBSA free energy calculation. Our result shows that the electrostatic interactions between polar groups on the 150-loop and the charged groups of the ligands play a key role on the binding selectivity. In particular, ligands having a small positively charged group favor binding to the closed conformation of H5N1 NA, while those having a large positively charged group generally prefer binding to the open conformation. Our analysis suggests that it may be possible to design new inhibitors with large basic groups that are selective for the open conformation and thereby have stronger binding affinity to H5N1 neuraminidase.
It was suggested that the open conformation of the 150-loop of H5N1 avian influenza neuraminidase is intrinsically lower in energy than the closed conformation and that oseltamivir (tamiflu) favors binding to the closed conformation through a relatively slow conformational change [Russell, R. J. Nature2006, 443, 45−49]. In the present work, a systematic computational study is performed to investigate the binding mechanism of five ligands to H5N1 neuraminidase (H5N1 NA) with the 150-loop in both open and closed conformations through molecular docking, molecular dynamics simulations, and MM/PBSA free energy calculation. Our result shows that the electrostatic interactions between polar groups on the 150-loop and the charged groups of the ligands play a key role on the binding selectivity. In particular, ligands having a small positively charged group favor binding to the closed conformation of H5N1 NA, while those having a large positively charged group generally prefer binding to the open conformation. Our analysis suggests that it may be possible to design new inhibitors with large basic groups that are selective for the open conformation and thereby have stronger binding affinity to H5N1 neuraminidase.
http://pubs.acs.org/doi/abs/10.1021/jp1030224
Pei Wang? and John Z. H. Zhang*???
Institute of Theoretical and Computational Science, and State Key Laboratory of Precision Spectroscopy, Department of Physics, East China Normal University, Shanghai 200062, China, and Department of Chemistry, New York University, New York, New York 10003
J. Phys. Chem. B, Article ASAP
DOI: 10.1021/jp1030224
Publication Date (Web): September 22, 2010
Copyright ? 2010 American Chemical Society
It was suggested that the open conformation of the 150-loop of H5N1 avian influenza neuraminidase is intrinsically lower in energy than the closed conformation and that oseltamivir (tamiflu) favors binding to the closed conformation through a relatively slow conformational change [Russell, R. J. Nature2006, 443, 45−49]. In the present work, a systematic computational study is performed to investigate the binding mechanism of five ligands to H5N1 neuraminidase (H5N1 NA) with the 150-loop in both open and closed conformations through molecular docking, molecular dynamics simulations, and MM/PBSA free energy calculation. Our result shows that the electrostatic interactions between polar groups on the 150-loop and the charged groups of the ligands play a key role on the binding selectivity. In particular, ligands having a small positively charged group favor binding to the closed conformation of H5N1 NA, while those having a large positively charged group generally prefer binding to the open conformation. Our analysis suggests that it may be possible to design new inhibitors with large basic groups that are selective for the open conformation and thereby have stronger binding affinity to H5N1 neuraminidase.
It was suggested that the open conformation of the 150-loop of H5N1 avian influenza neuraminidase is intrinsically lower in energy than the closed conformation and that oseltamivir (tamiflu) favors binding to the closed conformation through a relatively slow conformational change [Russell, R. J. Nature2006, 443, 45−49]. In the present work, a systematic computational study is performed to investigate the binding mechanism of five ligands to H5N1 neuraminidase (H5N1 NA) with the 150-loop in both open and closed conformations through molecular docking, molecular dynamics simulations, and MM/PBSA free energy calculation. Our result shows that the electrostatic interactions between polar groups on the 150-loop and the charged groups of the ligands play a key role on the binding selectivity. In particular, ligands having a small positively charged group favor binding to the closed conformation of H5N1 NA, while those having a large positively charged group generally prefer binding to the open conformation. Our analysis suggests that it may be possible to design new inhibitors with large basic groups that are selective for the open conformation and thereby have stronger binding affinity to H5N1 neuraminidase.
http://pubs.acs.org/doi/abs/10.1021/jp1030224