On the Lower Susceptibility of Oseltamivir to Influenza Neuraminidase Subtype N1 than Those in N2 and N9
| Autor: | Pornthep Sompornpisut, Maturos Malaisree, Vudhichai Parasuk, Supot Hannongbua, Somsak Pianwanit, Panita Decha, Ornjira Aruksakunwong |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Stereochemistry Biophysics Neuraminidase Biophysical Theory and Modeling Antiviral Agents Catalysis Substrate Specificity Molecular dynamics Oseltamivir Side chain Computer Simulation Binding site Binding Sites Dose-Response Relationship Drug Influenza A Virus H5N1 Subtype biology Chemistry Hydrogen bond Solvation Ligand (biochemistry) Enzyme Activation Enzyme binding Crystallography Models Chemical biology.protein Protein Binding |
| Zdroj: | Biophysical Journal. 92(3):798-807 |
| ISSN: | 0006-3495 |
| DOI: | 10.1529/biophysj.106.092528 |
| Popis: | Aiming to understand, at the molecular level, why oseltamivir (OTV) cannot be used for inhibition of human influenza neuraminidase subtype N1 as effectively as for subtypes N2 and N9, molecular dynamics simulations were carried out for the three complexes, OTV-N1, OTV-N2, and OTV-N9. The three-dimensional OTV-N2 and OTV-N9 initial structures were represented by the x-ray structures, whereas that of OTV-N1, whose x-ray structure is not yet solved, was built up using the aligned sequence of H5N1 isolated from humans in Thailand with the x-ray structure of the N2-substrate as the template. In comparison to the OTV-N2 and OTV-N9 complexes, dramatic changes were observed in the OTV conformation in the OTV-N1 complex in which two of its bulky side chains, N-acethyl (−NHAc) and 1-ethylproxy group (−OCHEt2), were rotated to adjust the size to fit into the N1 catalytic site. This change leads directly to the rearrangements of the OTV’s environment, which are i), distances to its neighbors, W-178 and E-227, are shorter whereas those to residues R-224, E-276, and E-292 are longer; ii), hydrogen bonds to the two nearest neighbors, R-224 and E-276, are still conserved in distance and number as well as percentage occupation; iii), the calculated ligand/enzyme binding free energies of −7.20, −13.44, and −13.29kcal/mol agree with their inhibitory activities in terms of the experimental IC50 of 36.1–53.2nM, 1.9–2.7nM, and 9.5–17.7nM for the OTV-N1, OTV-N2, and OTV-N9 complexes, respectively; and iv), hydrogen-bond breaking and creation between the OTV and neighborhood residues are accordingly in agreement with the ligand solvation/desolvation taking place in the catalytic site. |
| Databáze: | OpenAIRE |
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