Interaction Analysis of FABP4 Inhibitors by X-ray Crystallography and Fragment Molecular Orbital Analysis.
X-ray crystal structural determination of FABP4 in complex with four inhibitors revealed the complex binding modes, and the resulting observations led to improvement of the inhibitory potency of FABP4 inhibitors. However, the detailed structure-activity relationship (SAR) could not be explained from these structural observations. For a more detailed understanding of the interactions between FABP4 and inhibitors, fragment molecular orbital analyses were performed. These analyses revealed that the total interfragment interaction energies of FABP4 and each inhibitor correlated with the ranking of the K i value for the four inhibitors. Furthermore, interactions between each inhibitor and amino acid residues in FABP4 were identified. The oxygen atom of Lys58 in FABP4 was found to be very important for strong interactions with FABP4. These results might provide useful information for the development of novel potent FABP4 inhibitors.
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Uno
U
Tagami
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Kazutoshi
K
Takahashi
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Shunsuke
S
Igarashi
Research Institute, Ajinomoto Pharmaceuticals Co., Ltd. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Chieko
C
Ejima
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Tomomi
T
Yoshida
Research Institute, Ajinomoto Pharmaceuticals Co., Ltd. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Sen
S
Takeshita
Research Institute, Ajinomoto Pharmaceuticals Co., Ltd. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Wataru
W
Miyanaga
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Masayuki
M
Sugiki
Research Institute, Ajinomoto Pharmaceuticals Co., Ltd. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Munetaka
M
Tokumasu
Research Institute, Ajinomoto Pharmaceuticals Co., Ltd. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Toshihiro
T
Hatanaka
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Tatsuki
T
Kashiwagi
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Kohki
K
Ishikawa
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Hiroshi
H
Miyano
Institute for Innovation, Ajinomoto Co., Inc. , 1-1 Suzuki-cho, Kawasaki 210-8681, Japan.
Toshimi
T
Mizukoshi
FABP; FMO; X-ray crystal structure; aP2; inhibitor