Hydration of ligands of influenza virus neuraminidase studied by the fragment molecular orbital method.
The fragment molecular orbital (FMO) method was applied to quantum chemical calculations of neuramic acid, the natural substrate of the influenza virus neuraminidase, and two of its competitive inhibitors, Oseltamivir (Tamiful(®)) and Zanamivir (Relenza(®)), to investigate their hydrated structures and energetics. Each of the three ligands was immersed in an explicit water solvent, geometry-optimized by classical MM and QM/MM methods, and subjected to FMO calculations with 2-, 3-, and 4-body corrections under several fragmentation options. The important findings were that QM/MM optimization was preferable to obtain reliable hydrated structures of the ligands, that the 3-body correction was important for quantitative evaluation of the solvation energy, and that the dehydration effect was most remarkable near the hydrophobic sections of the ligands. In addition, the hydration energy calculated by the explicit solvent was compared with the hydration free energy calculated by the implicit solvent via the Poisson-Boltzmann equation, and the two showed a fairly good correlation. These findings will serve as useful information for rapid drug design.
Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan.
Kana
K
Tokuda
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
Chiduru
C
Watanabe
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
Yoshio
Y
Okiyama
Department of Chemistry and Research Center for Smart Molecules, Faculty of Science, Rikkyo University, 3-34-1 Nishi-Ikebukuro, Toshima-ku, Tokyo 171-8501, Japan; Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan.
Yuji
Y
Mochizuki
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan; School of Dentistry at Matsudo, Nihon University, 2-870-1 Sakaecho-Nishi, Matsudo, Chiba 271-8587, Japan. Electronic address: fukuzawa.kaori@nihon-u.ac.jp.
Kaori
K
Fukuzawa
Biomedical Research Institute, AIST Tsukuba Central 2, Tsukuba, Ibaraki 305-8568, Japan.
Yuto
Y
Komeiji
D006860:Hydrogen Bonding; D009980:Influenza A virus / Q000201:enzymology*; D008024:Ligands; D008958:Models, Molecular; D009439:Neuraminidase / Q000737:chemistry* / Q000378:metabolism*; D011789:Quantum Theory; D015203:Reproducibility of Results; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*; D053243:Zanamivir / Q000737:chemistry
D008024:Ligands; D012997:Solvents; D014867:Water; D009439:Neuraminidase; D053243:Zanamivir
Drug design; Fragment molecular orbital method; Hydration of ligands; Influenza virus neuraminidase; N-acetylneuraminic acid; Oseltamivir; Solvation energy; Zanamivir