Selective Binding of Antiinfluenza Drugs and Their Analogues to 'Open' and 'Closed' Conformations of H5N1 Neuraminidase

It was suggested that the open conformation of the 150-loop of H5N1 I 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. Nature 2006, 443, 45-491. In the present work, a systematic computational study is performed to investigate the binding mechanism of five ligands to H5N1 neurarninidase (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 I 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 I neuraminidase.