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Structure Activity Relationships of Quinoxalin-2-one Derivatives as Platelet-Derived Growth Factor-β Receptor (PDGFβ R) Inhibitors, Derived from Molecular Modeling
http://hdl.handle.net/2297/9908
http://hdl.handle.net/2297/9908f6ca1b4f-a27a-4b56-9dac-c00098cbc444
名前 / ファイル | ライセンス | アクション |
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HO-PR-MIYAMOTO-K-982.pdf (2.8 MB)
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Item type | 学術雑誌論文 / Journal Article(1) | |||||
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公開日 | 2017-10-05 | |||||
タイトル | ||||||
タイトル | Structure Activity Relationships of Quinoxalin-2-one Derivatives as Platelet-Derived Growth Factor-β Receptor (PDGFβ R) Inhibitors, Derived from Molecular Modeling | |||||
言語 | ||||||
言語 | eng | |||||
資源タイプ | ||||||
資源タイプ識別子 | http://purl.org/coar/resource_type/c_6501 | |||||
資源タイプ | journal article | |||||
著者 |
Mori, Yoshikazu
× Mori, Yoshikazu× Hirokawa, Takatsugu× Aoki, Katsuyuki× Satomi, Hisanori× Takeda, Shuichi× Aburada, Masaki× Miyamoto, Ken-ichi |
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提供者所属 | ||||||
内容記述タイプ | Other | |||||
内容記述 | 金沢大学附属病院薬剤部 | |||||
書誌情報 |
Chemical and Pharmaceutical Bulletin 巻 56, 号 5, p. 682-687, 発行日 2008-01-01 |
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ISSN | ||||||
収録物識別子タイプ | ISSN | |||||
収録物識別子 | 0009-2363 | |||||
NCID | ||||||
収録物識別子タイプ | NCID | |||||
収録物識別子 | AA00602100 | |||||
DOI | ||||||
関連タイプ | isIdenticalTo | |||||
識別子タイプ | DOI | |||||
関連識別子 | 10.1248/cpb.56.682 | |||||
出版者 | ||||||
出版者 | 日本薬学会 | |||||
抄録 | ||||||
内容記述タイプ | Abstract | |||||
内容記述 | We previously reported a quinoxalin-2-one compound (Compound 1) that had inhibitory activity equivalent to existing platelet-derived growth factor-β receptor (PDGFβ R) inhibitors. Lead optimization of Compound 1 to increase its activity and selectivity, using structural information regarding PDGFβ R-ligand interactions, is urgently needed. Here we present models of the PDGFβ R kinase domain complexed with quinoxalin-2-one derivatives. The models were constructed using comparative modeling, molecular dynamics (MD) and ligand docking. In particular, conformations derived from MD, and ligand binding site information presented by α-spheres in the pre-docking processing, allowed us to identify optimal protein structures for docking of target ligands. By carrying out molecular modeling and MD of PDGFβ R in its inactive state, we obtained two structural models having good Compound 1 binding potentials. In order to distinguish the optimal candidate, we evaluated the structural activity relationships (SAR) between the ligand-binding free energies and inhibitory activity values (IC50 values) for available quinoxalin-2-one derivatives. Consequently, a final model with a high SAR was identified. This model included a molecular interaction between the hydrophobic pocket behind the ATP binding site and the substitution region of the quinoxalin-2-one derivatives. These findings should prove useful in lead optimization of quinoxalin-2-one derivatives as PDGFb R inhibitors. © 2008 Pharmaceutical Society of Japan. | |||||
著者版フラグ | ||||||
出版タイプ | VoR | |||||
出版タイプResource | http://purl.org/coar/version/c_970fb48d4fbd8a85 |