title: Correlation analyses on binding affinity of sialic acid analogues and anti-influenza drugs with human neuraminidase using ab initio MO calculations on their complex structures--LERE-QSAR analysis (IV).
abstract: We carried out full ab initio fragment molecular orbital (FMO) calculations for complexes comprising human neuraminidase-2 (hNEU2) and sialic acid analogues including anti-influenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) in order to examine the variation in the observed inhibitory activity toward hNEU2 at the atomic and electronic levels. We recently proposed the LERE (linear expression by representative energy terms)-QSAR (quantitative structure-activity relationship) procedure. LERE-QSAR analysis quantitatively revealed that the complex formation is driven by hydrogen-bonding and electrostatic interaction of hNEU2 with sialic acid analogues. The most potent inhibitory activity, that of zanamivir, is attributable to the strong electrostatic interaction of a positively charged guanidino group in zanamivir with negatively charged amino acid residues in hNEU2. After we confirmed that the variation in the observed inhibitory activity among sialic acid analogues is excellently reproducible with the LERE-QSAR equation, we examined the reason for the remarkable difference between the inhibitory potencies of oseltamivir as to hNEU2 and influenza A virus neuraminidase-1 (N1-NA). Several amino acid residues in close contact with a positively charged amino group in oseltamivir are different between hNEU2 and N1-NA. FMO-IFIE (interfragment interaction energy) analysis showed that the difference in amino acid residues causes a remarkably large difference between the overall interaction energies of oseltamivir with hNEU2 and N1-NA. The current results will be useful for the development of new anti-influenza drugs with high selectivity and without the risk of adverse side effects.
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: Hiroshi
authors.initials: H
authors.lastname: Matoba
authors.forename: Masataka
authors.initials: M
authors.lastname: Harada
authors.forename: Tatsusada
authors.initials: T
authors.lastname: Yoshida
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuji
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Hirokawa
authors.forename: Kohji
authors.initials: K
authors.lastname: Itoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Chuman
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D004583:Electrons; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000201:enzymology*; D056004:Molecular Dynamics Simulation; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives* / Q000378:metabolism*; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D011789:Quantum Theory; D055672:Static Electricity; D013816:Thermodynamics; D053243:Zanamivir / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid; D053243:Zanamivir