Drug sensitivity prediction for anaplastic lymphoma kinase mutants using molecular dynamics simulation and its informatics analysis

• Project/Area Number: 18K06594
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: Araki Mitsugu 京都大学, 医学研究科, 特定准教授 (10452492)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 非小細胞肺がん / ALKキナーゼ / 薬剤耐性変異 / 分子動力学シミュレーション / タンパク質-化合物結合親和性 / 統計解析 / 薬剤応答性 / 分子動力学計算 / 遺伝子変異

Outline of Final Research Achievements

In this study, we focused on drug resistance of non-small cell lung cancer (NSCLC), and developed a computational method for predicting mutation-induced drug sensitivities of anaplastic lymphoma kinase (ALK) inhibitors.
First, targeting three ALK inhibitors (crizotinib, alectinib, ceritinib), we performed molecular dynamics (MD) simulation of the ALK mutant-inhibitor complex (180 single mutants x 3 drugs) and computed the binding free energies of these drugs for each mutant. Next, three ALK mutants with reduced binding affinity for all the drugs were extracted as candidates for multidrug-resistant mutants. When the drug responsiveness of these mutants was experimentally measured, those of two mutants was reduced for all the drugs.

Academic Significance and Societal Importance of the Research Achievements

近年、患者個人のゲノムに基づいて最適な治療を提供する「個別化医療」が注目されているものの、患者のゲノム配列で同定された遺伝子変異の90％以上は機能的意義が不明である。本研究成果は、どの変異ががんの薬剤耐性化に寄与しているのかを推定可能にする点で、計算科学駆動型医療の先駆けとなる取り組みである。更に、本法によって推定した薬剤耐性の分子メカニズム及び変異体の立体構造情報は、耐性を克服する新薬の分子設計に役立つと期待される。

Research Products

• [Journal Article] Exploring ligand binding pathways on proteins using hypersound-accelerated molecular dynamics (2021)
  • Author(s): Araki Mitsugu、Matsumoto Shigeyuki、Bekker Gert-Jan、Isaka Yuta、Sagae Yukari、Kamiya Narutoshi、Okuno Yasushi
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41467-021-23157-1
  • NAID: 120007041708
  • Peer Reviewed / Open Access
• [Journal Article] Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer (2021)
  • Author(s): Mizuta Hayato、Okada Koutaroh、Araki Mitsugu、Adachi Jun、Takemoto Ai、Kutkowska Justyna、Maruyama Kohei、Friboulet Luc、Katayama Kazuhiro、Ma Biao、Sasakura Yoko、Sagae Yukari、Kukimoto-Niino Mutsuko、Shirouzu Mikako、Takagi Satoshi、Simizu Siro、Nishio Makoto、Okuno Yasushi、Fujita Naoya、Katayama Ryohei, et al
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 1261-1261
  • DOI: 10.1038/s41467-021-21396-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity (2021)
  • Author(s): Yoshizawa Takahiro、Uchibori Ken、Araki Mitsugu、Matsumoto Shigeyuki、Ma Biao、Kanada Ryo、Seto Yosuke、Oh-hara Tomoko、Koike Sumie、Ariyasu Ryo、Kitazono Satoru、Ninomiya Hironori、Takeuchi Kengo、Yanagitani Noriko、Takagi Satoshi、Kishi Kazuma、Fujita Naoya、Okuno Yasushi、Nishio Makoto、Katayama Ryohei
  • Journal Title: npj Precision Oncology Volume: 5 Issue: 1 Pages: 32-32
  • DOI: 10.1038/s41698-021-00170-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] E487K-Induced Disorder in Functionally Relevant Dynamics of Mitochondrial Aldehyde Dehydrogenase 2. (2020)
  • Author(s): Matsumoto S, Araki M, Isaka Y, Ono F, Hirohashi K, Ohashi S, Muto M, Okuno Y.
  • Journal Title: Biophysical Journal Volume: 119(3) Pages: 628-637
  • Peer Reviewed
• [Journal Article] Landscape and function of multiple mutations within individual oncogene (2020)
  • Author(s): Yuki Saito, Junji Koya, Mitsugu Araki, Yasunori Kogure, Sumito Shingaki, Mariko Tabata, Marni B. McClure, Kota Yoshifuji, Shigeyuki Matsumoto, Yuta Isaka, Hiroko Tanaka, Takanori Kanai, Satoru Miyano, Yuichi Shiraishi, Yasushi Okuno, Keisuke Kataoka
  • Journal Title: Nature Volume: 582 Pages: 95-99
  • Peer Reviewed
• [Journal Article] Improvement in predicting drug sensitivity changes associated with protein mutations using a molecular dynamics based alchemical mutation method (2020)
  • Author(s): Fumie Ono, Shuntaro Chiba, Yuta Isaka, Shigeyuki Matsumoto, Biao Ma, Ryohei Katayama, Mitsugu Araki, Yasushi Okuno
  • Journal Title: Scientific Reports Volume: 10(1) Pages: 1-10
  • Peer Reviewed
• [Journal Article] Prediction of ALK mutations mediating ALK-TKIs resistance and drug re-purposing to overcome the resistance (2019)
  • Author(s): Okada K, Araki M, Sakashita T, Ma B, Kanada R, Yanagitani N, Horiike A, Koike S, Oh-hara T, Watanabe K, Tamai K, Maemondo M, Nishio M, Ishikawa T, Okuno Y, Fujita N, Katayama R
  • Journal Title: EBioMedicine Volume: 41 Pages: 105-119
  • NAID: 120006892063
  • Peer Reviewed
• [Journal Article] Structural modification of indomethacin toward selective inhibition of COX-2 with a significant increase in van der Waals contributions (2019)
  • Author(s): Ikeda A, Funakoshi E, Araki M, Ma B, Karuo Y, Tarui A, Sato K, Okuno Y, Kawai K, Omote M.
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 27(9) Pages: 1789-1794
  • Peer Reviewed
• [Journal Article] Dynamic Docking of a Medium Sized Molecule to its Receptor by Multicanonical MD Simulations (2019)
  • Author(s): Bekker, G; Araki, M; Oshima, K; Okuno, Y; Kamiya, N
  • Journal Title: The Journal of Physical Chemistry B Volume: 123(11) Pages: 2479-2490
  • Peer Reviewed
• [Journal Article] Improving the Accuracy of Protein-Ligand Binding Mode Prediction Using a Molecular Dynamics-Based Pocket Generation Approach (2018)
  • Author(s): Araki Mitsugu、Iwata Hiroaki、Ma Biao、Fujita Atsuto、Terayama Kei、Sagae Yukari、Ono Fumie、Tsuda Koji、Kamiya Narutoshi、Okuno Yasushi
  • Journal Title: Journal of Computational Chemistry Volume: 39 Issue: 32 Pages: 2679-2689
  • DOI: 10.1002/jcc.25715
  • Peer Reviewed
• [Journal Article] 非小細胞肺がん（NSCLC）における薬剤耐性獲得メカニズムの予測. (2018)
  • Author(s): 荒木望嗣, 奥野恭史
  • Journal Title: がん分子標的治療 Volume: 16 Pages: 53-58
• [Presentation] A multiscale molecular simulation approach to assess the effects of mutations on functional activity and drug sensitivity in kinases (2022)
  • Author(s): Mitsugu Araki and Yasushi Okuno
  • Organizer: Spring 2022 ACS National Meeting
  • Int'l Joint Research
• [Presentation] プレシジョンメディスンを加速する創薬ビッグデータ統合システムの推進 (2022)
  • Author(s): 荒木望嗣, 奥野恭史
  • Organizer: 富岳成果創出加速プログラム 研究交流会
• [Presentation] スパコンを用いたタンパク質-医薬品結合親和性・結合解離パスウェイの高精度予測 (2022)
  • Author(s): 荒木望嗣
  • Organizer: 第429回CBI学会研究講演会
• [Presentation] Effect of conformational flexibility of protein-ligand binding free energy computation and its significance in predicting mutation-induced drug sensitivity changes in oncogenic kinases (2020)
  • Author(s): Mitsugu Araki and Yasushi Okuno
  • Organizer: ACS Fall 2020 Virtual Meeting & Expo
  • Int'l Joint Research
• [Presentation] スパコンを用いたタンパク質-化合物結合親和性の高精度予測と医療・創薬への応用 (2020)
  • Author(s): 荒木望嗣, 奥野恭史
  • Organizer: 第48回構造活性相関シンポジウム
  • Invited
• [Presentation] Protein-drug binding mode prediction from the apo-protein structure using a molecular dynamics-based pocket generation approach (2020)
  • Author(s): Mitsugu Araki and Yasushi Okuno
  • Organizer: Biophysical Society 64th annual meeting
• [Presentation] Protein-ligand binding mode prediction from the apo-protein structure using a molecular dynamics-based pocket generation approach (2019)
  • Author(s): Mitsugu Araki and Yasushi Okuno
  • Organizer: Fall 2019 ACS National Meeting
• [Presentation] DRUG RESISTANCE INDUCED BY LOCAL AND ALLOSTERIC CONFORMATIONAL CHANGES IN ONCOGENIC TYROSINE KINASES. (2019)
  • Author(s): Mitsugu Araki and Yasushi Okuno
  • Organizer: Biophysical Society 63rd annual meeting
  • Int'l Joint Research
• [Presentation] Drug resistance acquired by local and allosteric conformational changes in oncogenic tyrosine kinases (2019)
  • Author(s): Mitsugu Araki and Yasushi Okuno
  • Organizer: Spring 2019 ACS National Meeting
  • Int'l Joint Research