title: Computational design of novel, high-affinity neuraminidase inhibitors for H5N1 avian influenza virus.
abstract: To propose more effective inhibitors for neuraminidase subtype N1, four potential inhibitors were molecularly designed by substitution at the C(3) position of oseltamivir to give additional interaction with the 150-cavity, since a new cavity known as the '150-cavity' adjacent to the well-known active site has been found in the neuraminidase subtype N1. We calculated the binding free energy of both oseltamivir and the newly designed inhibitors for subtype N1, using molecular dynamics simulations, to predict their drug effectiveness. When the drug effectiveness of four potential inhibitors is compared with that of oseltamivir, we discovered a highly potent neuraminidase inhibitor, which exhibited much higher binding affinity to subtype N1 than oseltamivir (-17.77 vs. -8.06 kcal/mol).
authors.affiliation: Department of Materials Science and Engineering, Seoul National University, Kwanak-ku Seoul 151-742, Republic of Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Won Ho
authors.initials: WH
authors.lastname: Jo
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D001682:Biological Availability; D017076:Computer-Aided Design; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000201:enzymology*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053139:Oseltamivir / Q000378:metabolism / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D053139:Oseltamivir; D009439:Neuraminidase