Interaction Analysis of FABP4 Inhibitors by X-ray Crystallography and Fragment Molecular Orbital Analysis

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• 作者：Uno Tagami ; Kazutoshi Takahashi ; Shunsuke Igarashi ; Chieko Ejima ; Tomomi Yoshida ; Sen Takeshita ; Wataru Miyanaga ; Masayuki Sugiki ; Munetaka Tokumasu ; Toshihiro Hatanaka ; Tatsuki Kashiwagi ; Kohki Ishikawa ; Hiroshi Miyano ; Toshimi Mizukoshi
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：7
• 期：4
• 页码：435-439
• 全文大小：346K
• 年卷期：0
• ISSN：1948-5875

文摘

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.