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

2021 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

創薬計算科学

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。