2022 Fiscal Year Final Research Report
Development of novel computational method for identification of druggable cryptic pocket on protein surface
| Project/Area Number |
20K15974
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 47020:Pharmaceutical analytical chemistry and physicochemistry-related
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| Research Institution | Kitasato University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | インシリコ創薬 / フラグメントベース創薬 / フラグメントマッピング / バーチャルスクリーニング / ポケット構造予測 / cryptic pocket |
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| Outline of Final Research Achievements |
Cryptic ligand binding sites, which are not evident in the unliganded structures, are beneficial in tackling with difficult but attractive drug targets. However, cryptic pockets have thus far not been rationally pursued in the early stages of drug development. In this study, we optimized the protocol of our in silico fragment mapping method for discovery of the cryptic pockets, and then successfully identified the lead compounds for the development of the inhibitors for several drug targets. These results demonstrated the utility of our in silico fragment mapping method as a novel computational fragment-based drug design (FBDD) methodology targeting the cryptic pockets.
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| Free Research Field |
計算科学
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| Academic Significance and Societal Importance of the Research Achievements |
Cryptic pocket は従来の薬物標的より柔軟性の高いアロステリック部位やタンパク質-タンパク質間相互作用界面に対する創薬や機能解析に重要である。これまでにcryptic pocket探索のための計算手法が複数開発されてきたが、インシリコ・フラグメントマッピング法は従来法とは原理が異なるため、標的ごとの使い分けや適切な手法の組み合わせといった相補的な利用が想定される。これにより、これまでアンドラッガブルと見なされていた高難度標的に対する創薬の加速や、過渡的なポケット形成や準安定構造といった様々な生命現象に関わるタンパク質の動的構造解析への進展が期待できる。
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