Development of a method to discover high affinity ligands using molecular dynamics simulation

• Project/Area Number: 22590110
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kinki University
• Principal Investigator: NAKANISHI Isao 近畿大学, 薬学部, 教授 (10362576)
• Co-Investigator(Kenkyū-buntansha): KITAURA Kazuo 神戸大学, システム情報科学研究科, 特命教授 (30132723)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 生物活性物質 / 計算化学 / 熱力学積分法 / 水和エネルギー / 結合自由エネルギー / CK2 / 自由エネルギー摂動法

Research Abstract

The free energy perturbation (FEP)/Thermodynamic integration (TI) methods were applied to explore high affinity ligands with a small structural change to a known ligand. By changing various calculation conditions, affinity differences among protein kinase CK2 ligands could be reproduced with high accuracy. Possibly novel potent ligands for CK2 protein were discovered by exhaustive prediction of synthetic feasible ligands. The optimized calculation condition gives good reproducibility and this prediction method is useful in drug discovery.

Research Products

• [Journal Article] An Efficient Method to Evaluate Intermolecular Interaction Energies in Large Systems Using Overlapping Multicenter ONIOM and the Fragment Molecular Orbital Method. (2012)
  • Author(s): N. Asada, D. G. Fedorov, K. Kitaura, I. Nakanishi, K. M. Merz.
  • Journal Title: J. Phys. Chem. Lett. Volume: 3 Issue: 18 Pages: 2604-2610
  • DOI: 10.1021/jz3010688
  • Peer Reviewed
• [Journal Article] Subtle structural changes in tetrahydro- quinolines, a new class of nonsteroidal selective androgen receptor modulators, induce different functions. (2012)
  • Author(s): N. Nagata, K. Kawai, I. Nakanishi
  • Journal Title: J. Chem. Inf. Model. Volume: 52 Issue: 8 Pages: 2257-2264
  • DOI: 10.1021/ci300219g
  • Peer Reviewed
• [Journal Article] Structure-based Design of Novel Potent CK2 Inhibitors with Phenyl-azole Scaffolds. (2012)
  • Author(s): Z. Hou, I. Nakanishi, T. Kinoshita, Y. Takei, M. Yasue, R. Misu, Y. Suzuki, S. Nakamura, T. Kure, H. Ohno, K. Murata, K. Kitaura, A. Hirasawa, G. Tsujimoto, S. Oishi, N. Fujii.
  • Journal Title: J. Med. Chem. Volume: 55 Issue: 6 Pages: 2899-2903
  • DOI: 10.1021/jm2015167
  • Peer Reviewed
• [Journal Article] Design and synthesis of a novel class of CK2 inhibitors: application of copper- and gold-catalysed cascade reactions for fused nitrogen heterocycles. (2012)
  • Author(s): Yamato Suzuki
  • Journal Title: Org. Biomol. Chem. Volume: 10 Pages: 4907-4915
  • Peer Reviewed
• [Journal Article] Subtle structural changes in tetrahydroquinolines, a new class of nonsteroidal selective androgen receptor modulators, induce different functions. (2012)
  • Author(s): Naoya Nagata
  • Journal Title: J. Chem. Inf. Model. Volume: 52 Pages: 2257-2264
  • Peer Reviewed
• [Journal Article] In silico design, synthesis and evaluation of 3'-O-benzylated analogs of salacinol, a potent a-glucosidase inhibitor isolated from an Ayurvedic traditional medicine ‘‘Salacia’’. (2012)
  • Author(s): Genzoh Tanabe
  • Journal Title: Chem. Commun. Volume: 48 Pages: 8646-8648
  • Peer Reviewed
• [Journal Article] Role of the side chain stereochemistry in the α-glucosidase inhibitory activity of kotalanol, a potent natural α-glucosidase inhibitor, Part 2. (2012)
  • Author(s): Genzoh Tanabe
  • Journal Title: Bioorg. Med. Chem. Volume: 20 Pages: 6321-6334
  • Peer Reviewed
• [Journal Article] Structure0based Design of Novel Potent CK2 Inhibitors with Phenyl-azole Scaffolds (2012)
  • Author(s): Z.Hou, I.Nakanishi, et al
  • Journal Title: J.Med.Chem. Volume: 55 Pages: 2899-2903
  • Peer Reviewed
• [Journal Article] Importance of CH/π hydrogen bonds in recognition of the core motif in proline -recognition domains: An Ab initio fragment molecular orbital study. (2011)
  • Author(s): T. Ozawa, K. Okazaki, K. Kitaura
  • Journal Title: J. Comp. Chem. Volume: 32 Issue: 13 Pages: 2774-2782
  • DOI: 10.1002/jcc.21857
  • Peer Reviewed
• [Journal Article] A detailed thermodynamic profile of cyclopentyl and isopropyl derivatives binding to CK2 kinase. (2011)
  • Author(s): T. Kinoshita, Y. Sekiguchi, H. Fukada, T. Nakaniwa, T. Tada, S. Nakamura, K. Kitaura, H. Ohno, Y. Suzuki, A. Hirasawa, I. Nakanishi, G. Tsujimoto.
  • Journal Title: Mol. Cell Biochem. Volume: 356 Issue: 1-2 Pages: 97-105
  • DOI: 10.1007/s11010-011-0960-9
  • Peer Reviewed
• [Journal Article] Docking and SAR Studies of Salacinol Derivatives as α-Glucosidase Inhibitors. (2010)
  • Author(s): S. Nakamura, K. Takahira, G. Tanabe, T. Morikawa, M. Sakano, K. Ninomiya, M. Yoshikawa, O. Muraoka, I. Nakanishi
  • Journal Title: Bioorg. Med. Chem. Volume: 20 Issue: 15 Pages: 4420-4423
  • DOI: 10.1016/j.bmcl.2010.06.059
  • Peer Reviewed
• [Journal Article] SDOVS: A Solvent Dipole Ordering-Based Method for Virtual Screening. (2010)
  • Author(s): K. Murata, N. Nagata, I. Nakanishi, K. Kitaura
  • Journal Title: J. Comput. Chem. Volume: 31 Issue: 15 Pages: 2714-2722
  • DOI: 10.1002/jcc.21565
  • Peer Reviewed
• [Journal Article] Ligand Shape Emerges in Solvent Dipole Ordering Region at Ligand Binding Site of Protein. (2010)
  • Author(s): K. Murata, N. Nagata, I. Nakanishi, K. Kitaura
  • Journal Title: J. Comput. Chem. Volume: 31 Issue: 4 Pages: 791-796
  • DOI: 10.1002/jcc.21362
  • Peer Reviewed
• [Journal Article] Ligand Shape Emerges in Solvent Dipole Ordering Region at Ligand Binding Site of Protein (2010)
  • Author(s): K.Murata, N.Nagata, I.Nakanishi, K.Kitaura
  • Journal Title: J.Comput.Chem. Volume: 31 Pages: 791-796
  • Peer Reviewed
• [Journal Article] SDOVS : A Solvent Dipole Ordering-Based Method for Virtual Screening (2010)
  • Author(s): K.Murata, N.Nagata, I.Nakanishi, K.Kitaura
  • Journal Title: J.Comput.Chem. Volume: 31 Pages: 2714-2722
  • Peer Reviewed
• [Journal Article] Docking and SAR Studies of Salacinol Derivatives as a-Glucosidase Inhibitors (2010)
  • Author(s): S.Nakamura, K.Takahira, G.Tanabe, T.Morikawa, M.Sakano, K.Ninomiya, M.Yoshikawa, O.Muraoka, I.Nakanishi
  • Journal Title: Bioorg.Med.Chem. Volume: 20 Pages: 4420-4423
  • Peer Reviewed
• [Presentation] 「非経験的フラグメント分子軌道法を活用した高活性Protein Kinase CK2 阻害剤の設計」 (2012)
  • Author(s): 呉 竜英, 侯 増〓, 木下 誉富, 武井 義則, 安江 美里, 三須 良介, 鈴木 大和, 中村 真也, 大野 浩章, 村田 克美, 北浦 和夫, 平澤 明, 大石 真也, 藤井 信孝, 仲西 功
  • Organizer: 第40回構造活性相関シンポジウム
  • Place of Presentation: 愛知
• [Presentation] 「分子シミュレーションを用いたProtein Kinase CK2 阻害剤の活性予測」 (2012)
  • Author(s): 中西 伸介、森脇 寛智、中村 真也、西脇 敬二、仲西 功
  • Organizer: 第62回日本薬学会近畿支部大会
  • Place of Presentation: 兵庫
• [Presentation] Binding energy estimation of CK2 inhibitors by the ab initio-based fragment molecular orbital method. (2012)
  • Author(s): T. Kure, S. Nakamura, M. Kanemitsu, K. Murata, K. Kitaura, T. Kinoshita, Z. Hou, Y. Suzuki, H. Ohno, S. Oishi, N. Fujii, Y. Takei, M. Yasue, R. Misu, A. Hirasawa, G. Tsujimoto, I. Nakanishi.
  • Organizer: 22nd International Medicinal Chemistry Symposium 2012
  • Place of Presentation: Germany
• [Presentation] 「溶媒中における3(5)-Amino-5(3)-arylpyrazole誘導体の互変異性体存在比率の予測」 (2012)
  • Author(s): 呉 竜英、櫻井 淳史、西脇 敬二、中村 真也、仲西 功
  • Organizer: 第10回次世代を担う若手のためのフィジカル・ファーマフォーラム
  • Place of Presentation: 京都
• [Presentation] アザインドール骨格またはフェニルアゾール骨格を有する新規プロテインキナーゼCK2阻害剤の開発研究 (2012)
  • Author(s): 侯 増カ
  • Organizer: 第10回次世代を担う有機化学シンポジウム
  • Place of Presentation: 大阪
• [Presentation] 溶媒中における3(5)-Amino-5(3)-arylpyrazole誘導体の互変異性体存在比率の予測 (2012)
  • Author(s): 呉 竜英
  • Organizer: 第10回次世代を担う若手のためのフィジカル・ファーマフォーラム
  • Place of Presentation: 京都
• [Presentation] フェニルアゾール骨格を有する新規プロテインキナーゼCK2阻害剤の開発 (2012)
  • Author(s): 侯 増燁
  • Organizer: 第42回複素環化学討論会
  • Place of Presentation: 京都
• [Presentation] 非経験的フラグメント分子軌道法を活用した高活性Protein Kinase CK2 阻害剤の設計 (2012)
  • Author(s): 呉 竜英
  • Organizer: 第40回構造活性相関シンポジウム
  • Place of Presentation: 岡崎
• [Presentation] Binding energy estimation of CK2 inhibitors by the ab initio-based fragment molecular orbital method. (2012)
  • Author(s): Tatsuhide Kure
  • Organizer: 22nd International Medicinal Chemistry Symposium 2012
  • Place of Presentation: Berlin
• [Presentation] LynおよびLckキナーゼの阻害剤との相互作用解析 (2011)
  • Author(s): 宮野菜央、仲西功, 他
  • Organizer: 日本結晶学会年会
  • Place of Presentation: 北海道大学(北海道)
  • Year and Date: 2011-11-24
• [Presentation] FEP/TI法によるリガンド間のタンパク質結合自由エネルギー差の評価 (2011)
  • Author(s): 中尾佳人、仲西功, 他
  • Organizer: 第34回情報化学討論会
  • Place of Presentation: 長崎大学(長崎)
  • Year and Date: 2011-11-12
• [Presentation] MM/PBSA法によるCK2阻害剤ヘマテインの結合様式の予測 (2011)
  • Author(s): 永松和彦、仲西功, 他
  • Organizer: 第34回情報化学討論会
  • Place of Presentation: 長崎大学(長崎)
  • Year and Date: 2011-11-12
• [Presentation] Srcファミリーキナーゼ特異的阻害剤SU6656の選択性に関する計算化学的考察 (2011)
  • Author(s): 呉竜英、仲西功, 他
  • Organizer: 第9回次世代を担う若手のためのフィジカル・ファーマフォーラム
  • Place of Presentation: ホテル箱根アカデミー(神奈川)
  • Year and Date: 2011-09-11
• [Presentation] 分子力場計算におけるCl-π相互作用パラメータの作成と分子動力学計算による検証 (2011)
  • Author(s): 中尾佳人、中村真也、仲西功
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: ツインメッセ静岡(静岡県)
  • Year and Date: 2011-03-29
• [Presentation] Srcファミリーキナーゼ特異的阻害剤SU6656の選択性に関する計算化学的考察 (2011)
  • Author(s): 呉 竜英、中村 真也、宮野 菜央、多田 俊治、多賀 淳、仲西 功
  • Organizer: 第9回次世代を担う若手のためのフィジカル・ファーマフォーラム
  • Place of Presentation: 神奈川
• [Presentation] MM/PBSA法によるCK2阻害剤ヘマテインの結合様式の予測 (2011)
  • Author(s): 永松 和彦、中村 真也、木下 誉富、平澤 明、辻本 豪三、仲西 功
  • Organizer: 第34回情報化学討論会
  • Place of Presentation: 長崎
• [Presentation] FEP/TI法によるリガンド間のタンパク質結合自由エネルギー差の評価 (2011)
  • Author(s): 中尾 佳人、中村 真也、仲西 功
  • Organizer: 第34回情報化学討論会
  • Place of Presentation: 長崎
• [Presentation] 「分子力場計算におけるCl-π相互作用パラメータの作成と分子動力学計算による検証」 (2011)
  • Author(s): 中尾 佳人、中村 真也、仲西 功
  • Organizer: 日本薬学会第131年会
  • Place of Presentation: 静岡
• [Presentation] 分子シミュレーションを用いたProtein Kinase CK2 阻害剤の活性予測
  • Author(s): 中西 伸介
  • Organizer: 第62回日本薬学会近畿支部大会
  • Place of Presentation: 兵庫