Computer-aided rational molecular design of novel chitinase inhibitor

2008 Fiscal Year Final Research Report

• Project/Area Number: 19590043
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Physical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: GOUDA Hiroaki Kitasato University, 薬学部, 准教授 (60276160)
• Co-Investigator(Kenkyū-buntansha): HIRONO Shuichi 北里大学, 薬学部, 教授 (30146328) ; YAMAOTSU Noriyuki 北里大学, 薬学部, 助教 (60230322) ; NAKAGOME Izumi 北里大学, 薬学部, 助教 (30237242)
• Project Period (FY): 2007 – 2008
• Keywords: キチナーゼ / 阻害剤 / ドッキング計算 / 分子動力学 / 結合自由エネルギー

Research Abstract

キチナーゼ阻害剤には、抗真菌薬、殺虫剤および喘息治療薬としての可能性がある。そこで、我々は、環状ペプチド性キチナーゼ阻害剤、Argadin、と霊菌のキチナーゼB の複合体X線結晶構造に基づいたin silico創薬研究を行った。その結果、Argadinのペプチド性環状骨格を14員環マクロライド骨格で分子変換することで、新規な非ペプチド性キチナーゼ阻害剤が得られる可能性を示した。

Research Products

• [Journal Article] Computer-aided rational molecular design of argifin-derivatives with increased inhibitory activity against chitinase B from Serratia marcescens (2009)
  • Author(s): Gouda H, Sunazuka T, Iguchi K, Sugawara A, Hirose T, Noguchi Y, Saito Y, Yanai Y, Yamamoto T, Watanabe T, Shiomi K, Omura S, Hirono S
  • Journal Title: Bioorg. Med. Chem. Lett. 19(10) Pages: 2630-2633
  • Peer Reviewed
• [Journal Article] Structure-Based CoMFA As a Predictive Model-CYP2C9 Inhibitors As a Test Case (2009)
  • Author(s): Yasuo K, Yamaotsu N, Gouda H, Tsujishita H, Hirono S
  • Journal Title: J. Chem. Inf. Model 49(4) Pages: 853-864
  • Peer Reviewed
• [Journal Article] Design and synthesis of novel delta opioid receptor agonists and their pharmacologies (2009)
  • Author(s): Nagase H, Osa Y, Nemoto T, Fujii H, Imai M, Nakamura T, Kanemasa T, Kato A, Gouda H, Hirono S
  • Journal Title: Bioorg. Med. Chem. Lett. 19(10) Pages: 2792-2795
  • Peer Reviewed
• [Journal Article] Lys17 in the 'lasso' peptide lariatin A is responsible for anti-mycobacterial activity (2009)
  • Author(s): Iwatsuki M, Koizumi Y, Gouda H, Hirono S, Tomoda H, Omura S
  • Journal Title: Bioorg. Med. Chem. Lett. 19(10) Pages: 2888-2890
  • Peer Reviewed
• [Journal Article] Argifin ; Efficient Solid Phase Total Synthesis and Evalution of Analogues of Acyclic Peptide (2009)
  • Author(s): Sunazuka T, Sugawara A, Iguchi K, Hirose T, Nagai K, Noguchi Y, Saito Y, Yamamoto T, Ui H, Gouda H, Shiomi K, Watanabe T, Omura S
  • Journal Title: Bioorg. Med. Chem. 17(7) Pages: 2751-2758
  • Peer Reviewed
• [Journal Article] Structure Determination and Total Synthesis of Bottromycin A2 : A Potent Antibiotic against MRSA and VRE (2009)
  • Author(s): Shimamura H, Gouda H, Nagai K, Hirose T, Ichioka M, Furuya Y, Kobayashi Y, Hirono S, Sunazuka T, Omura S
  • Journal Title: Angew. Chem. -Int. Edit. 48 Pages: 914-917
  • Peer Reviewed
• [Journal Article] In silico multi-filter screening approaches for developing novel β -secretase inhibitors (2008)
  • Author(s): Fujimoto T, Matsushita Y, Gouda H, Yamaotsu N, Hirono S
  • Journal Title: Bioorg. Med. Chem. Lett. 18(9) Pages: 2771-2775
  • Peer Reviewed
• [Journal Article] Computational Analysis of the Binding Affinities of the Natural-Product Cyclopentapeptides Argifin and Argadin to Chitinase B from Serratia marcescens (2008)
  • Author(s): Gouda H, Yanai Y, Sugawara A, Sunazuka T, ?mura S, Hirono S.
  • Journal Title: Bioorg. Med. Chem. 16(7) Pages: 3565-3579
  • Peer Reviewed
• [Journal Article] MM-PBSA法を用いたキチナーゼ阻害剤ArgadinおよびArgifinの結合自由エネルギー計 (2008)
  • Author(s): 合田浩明, 柳井雄一, 広野修一
  • Journal Title: Pharma VISION NEWS No.11(March) Pages: 7-11
  • Peer Reviewed
• [Journal Article] Conformational behavior of oxygenated mycobacterial mycolic acids from Mycobacterium bovis BCG (2007)
  • Author(s): Villeneuve M, Kawai M, Watanabe M, Aoyagi Y, Hitotsuyanagi Y, Takeya K, Gouda H, Hirono S, Minnikin DE, Nakahara H
  • Journal Title: Biochim. Biophys. Acta. 1768(7) Pages: 1717-26
  • Peer Reviewed
• [Presentation] NMR 測定と高温分子動力学計算を組み合わせた抗生物質Bottromycin A2 の絶対構造決定 (2009)
  • Author(s): 合田浩明, 島村寛章, 長井賢一郎, 廣瀬友靖, 小林豊, 砂塚敏明, 大村智, 広野修一
  • Organizer: 日本薬学会第129 年会
  • Place of Presentation: 京都
  • Year and Date: 2009-03-27
• [Presentation] ヒト酸性キチナーゼを標的としたキチナーゼ阻害剤Argifinの理論的分子構造最適化 (2008)
  • Author(s): 寺嶋真一, 合田浩明, 広野修一
  • Organizer: 第27回メディシナルケミストリーシンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2008-11-26
• [Presentation] NMRおよび計算化学手法を用いたキチナーゼB とArgifin 由来ジペプチド阻害剤の相互作用解析 (2008)
  • Author(s): 合田浩明, 井口加奈美, 菅原章公, 山本剛, 廣瀬友靖, 塩見和朗, 砂塚敏明, 大村智, 広野修一
  • Organizer: 第27回メディシナルケミストリーシンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2008-11-26
• [Presentation] In silico 創薬技術を用いたキチナーゼ阻害剤Argifinの分子構造最適化 (2008)
  • Author(s): 合田浩明, 広野修一
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-28
• [Presentation] In silico創薬技術を用いた新規キチナーゼ阻害剤の論理的分子設計 (2008)
  • Author(s): 合田浩明, 広野修一
  • Organizer: 北里大学薬学部公開シンポジウム(ハイテクリサーチ・シンポジウム)創薬シーズ-発見から応用へ-
  • Place of Presentation: 東京
  • Year and Date: 2008-02-22
• [Presentation] In silico analysis of interaction between PI3K and its potent inhibitor ZSTK474 (2007)
  • Author(s): Satoh H, Koshimizu I, Yoshimi H, Watanabe T, Yaguchi S, Matsuno T, Gouda H, Yamori T, Hirono S
  • Organizer: 6th AFMC International Medicinal Chemistry Sympojium
  • Place of Presentation: Istanbul, Turkey
  • Year and Date: 20070708-11
• [Presentation] キチナーゼBに対するペプチド性阻害剤Argifin の相互作用解析とその誘導体の論理的分子設計 (2007)
  • Author(s): 合田浩明, 広野修一
  • Organizer: 第35回構造活性相関シンポジウム
  • Place of Presentation: 京都
  • Year and Date: 2007-11-16