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

作者：Phanich Jiraphorn; Rungrotmongkol Thanyada^*; Sindhikara Daniel; Phongphanphanee Saree; Yoshida Norio; Hirata Fumio^*; Kungwan Nawee; Hannongbua Supot

来源：Protein Science, 2016, 25(1): 147-158.

DOI：10.1002/pro.2718

• influenza B virus
• neuraminidase
• oseltamivir resistance
• 3D-RISM
• dehydration penalty

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.

• 出版日期2016-1