Enhanced structural sampling for allosteric drug design

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K14714
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biophysics
• Research Institution: Yokohama City University
• Principal Investigator: Kidera Akinori 横浜市立大学, 生命医科学研究科, 教授 (00186280)
• Research Collaborator: Moritsugu Kei ; Ando Minami ; Nishino Yoshihiko
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: タンパク質 / アロステリック相互作用 / 分子シミュレーション

Outline of Final Research Achievements

The rational design of allosteric drugs for protein kinase was attempted using a large-scale computational sampling method. The first target was MEK1, a Ser/Thr kinase. The docking study of all exhaustively sampled MEK1 structures revealed that a possible binding site was localized only at the back pocket of a known allosteric site. Since the limited variety of the binding mode was considered to be due to small flexibility of MEK1, we chose EGFR kinase for the second target, a receptor Tyr kinase exhibiting significantly large flexibility of the arrangement of the two lobes. The enhanced sampling of both apo and ATP-bound forms showed that ATP binding did not constrain the lobe motion. The ATP-bound form of EGFR kinase has a larger variety of binding modes depending on the lobe configuration, even though the sites are mostly in the back pocket. It was clearly demonstrated that large scale sampling method for the rational drug design.

Free Research Field

計算生物学

Academic Significance and Societal Importance of the Research Achievements

EGFR kinaseは、様々な薬剤を結合した147この立体構造情報がある。これらの構造多様性は、そのほとんどが結合している薬剤ではなく、結晶場、アミノ酸変異によって引き起こされており、それぞれの構造に適した薬剤が結合していることが分かり、薬剤設計における柔軟性の考慮が重要であることが示された。また、そのような薬剤結合部位の構造多様性が、局所的な構造変化では必ずしもなく、lobe間運動という全体構造によって起こっていることが示された。これによって、タンパク質リン酸化酵素における合理的薬剤設計の基本的枠組みができたものと考えている。