title: Correlation analyses on binding affinity of sialic acid analogues with influenza virus neuraminidase-1 using ab initio MO calculations on their complex structures.
abstract: We carried out full ab initio molecular orbital calculations on complexes between neuraminidase-1 (N1-NA) in the influenza A virus and a series of eight sialic acid analogues including oseltamivir (Tamiflu) in order to quantitatively examine the binding mechanism and variation in the inhibitory potency at the atomic and electronic levels. FMO-MP2-IFIE (interfragment interaction energy at the MP2 level of ab initio fragment molecular orbital calculations) analyses quantitatively revealed (1) that the complex formation is driven by strong electrostatic interactions of charged functional groups in the analogues with ionized amino acid residues and water molecules in the active site of N1-NA, and (2) that the variation in the inhibitory potency among the eight analogues is determined by the dispersion and/or hydrophobic interaction energies of the 3-pentyl ether and charged amino moieties in oseltamivir with certain residues and water molecules in the active site of N1-NA. The current results will be useful for the development of new antiinfluenza drugs with high potency against various subtypes of wild-type and drug-resistant NAs.
authors.affiliation: Institute of Health Biosciences, The University of Tokushima Graduate School, 1-78 Shomachi, Tokushima 770-8505, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Hitaoka
authors.forename: Masataka
authors.initials: M
authors.lastname: Harada
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Yoshida
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chuman
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D006801:Humans; D009980:Influenza A virus / Q000737:chemistry / Q000201:enzymology*; D008958:Models, Molecular; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000201:enzymology; D053139:Oseltamivir / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid