title: A 3D-RISM/RISM study of the oseltamivir binding efficiency with the wild-type and resistance-associated mutant forms of the viral influenza B neuraminidase.
abstract: The binding affinity of oseltamivir to the influenza B neuraminidase and to its variants with three single substitutions, E119G, R152K, and D198N, is investigated by the MM/3D-RISM method. The binding affinity or the binding free energy of ligand to receptor was found to be determined by a subtle balance of two major contributions that largely cancel out each other: the ligand-receptor interactions and the dehydration free energy. The theoretical results of the binding affinity of the drug to the mutants reproduced the observed trend in the resistivity, measured by IC50 ; the high-level resistance of E119G and R152K, and the low-level resistance of D198N. For E119G and R152K, reduction of the direct drug-target interaction, especially at the mutated residue, is the main source of high-level oseltamivir resistance. This phenomenon, however, is not found in the D198N strain, which is located in the framework of the active-site.
authors.affiliation: Department of Chemistry, Computational Chemistry Unit Cell, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
authors.forename: Jiraphorn
authors.initials: J
authors.lastname: Phanich
authors.affiliation: Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.|Ph.D. Program in Bioinformatics and Computational Biology, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
authors.forename: Thanyada
authors.initials: T
authors.lastname: Rungrotmongkol
authors.affiliation: Schrödinger, Inc, 120 West 45th Street, 17th Floor, New York, New York, 10036.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sindhikara
authors.affiliation: Department of Materials Science, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand.
authors.forename: Saree
authors.initials: S
authors.lastname: Phongphanphanee
authors.affiliation: Department of Chemistry, Graduate School of Sciences, Kyushu University, Fukuoka, 812-8581, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: College of Life Sciences, Ritsumeikan University, and Molecular Design Frontier Co. Ltd, Kusatsu, 525-8577, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Hirata
authors.affiliation: Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai, 50200, Thailand.
authors.forename: Nawee
authors.initials: N
authors.lastname: Kungwan
authors.affiliation: Department of Chemistry, Computational Chemistry Unit Cell, Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand.
authors.forename: Supot
authors.initials: S
authors.lastname: Hannongbua
mesh_terms: D001665:Binding Sites; D024882:Drug Resistance, Viral; D009981:Influenza B virus / Q000201:enzymology*; D056004:Molecular Dynamics Simulation; D009439:Neuraminidase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D053139:Oseltamivir / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D053139:Oseltamivir; D009439:Neuraminidase
keywords: 3D-RISM; dehydration penalty; influenza B virus; neuraminidase; oseltamivir resistance