BIOPHYSICAL THEORY AND MODELING |
On the Lower Susceptibility of Oseltamivir to Influenza
Neuraminidase Subtype N1 than those in N2 and N9
Ornjira Aruksakunwong 1, Maturos Malaisree 1, Panita Decha 1, Pornthep Sompornpisut 1, Vudhichai Parasuk 1, Somsak Pianwanit 1 and Supot Hannongbua 1*
1 Computational Chemistry Unit Cell, Chulalongkorn University
* To whom correspondence should be addressed. E-mail: supot.h{at}chula.ac.th.
Submitted on July 5, 2006
Revised on August 9, 2006
Accepted on 6 October 2006
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Abstract |
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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 3D OTV-N2 and OTV-N9 initial structures were represented by the X-ray structures while that of OTV-N1, which its 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 on 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 in order to adjust its 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, W178 and E227, are shorter while those to residues R224, E276 and E292 are longer. (ii) Hydrogen bonds to the two nearest neighbors, R224 and E276, 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 -13.29 kcal/mol agree with their inhibitory activities in terms of the experimental IC50 of 36.1 - 53.2 nM, 1.9 - 2.7 nM and 9.5 - 17.7 nM for the OTV-N1, OTV-N2 and OTV-N9 complexes, respectively. (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.
Key Words:
Human Influenza, MD simulation, Neuraminidase N1, Oseltamivir
