相互作用の熱力学情報に基づく低分子リガンド設計

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書誌事項

タイトル別名
  • Rational Fragment-design Method Based on a Thermodynamic Analysis
  • ソウゴ サヨウ ノ ネツリキガク ジョウホウ ニ モトズク テイブンシ リガンド セッケイ

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説明

  Thermodynamic analysis is an effective tool in drug design. Thermodynamic parameters of the interaction between a given ligand and its target protein can reveal the character of the ligand. In general, promising drug candidates achieve high affinity for a target protein through their contributions of both favorable enthalpy and entropy terms. It is, however, more difficult to optimize binding enthalpies than binding entropies in ligand-design; therefore, it is desirable to choose firstly a lead-compound based on its favorable binding enthalpy. In this study, we have explored the utility of this approach using anti-ciguatoxin antibody 10C9 as a model in the screening of a chemical library. We previously showed that 10C9 possesses an extraordinary large antigen-binding pocket that recognizes the antigen ciguatoxin by means of a favorable binding enthalpy. Here, among the many compounds tested, three of them could bind to the antigen-binding pocket of 10C9 with a few kcal/mol of favorable binding enthalpy. In addition, these compounds showed structural analogies with the proper antigen ciguatoxin: a comparison with other compounds which showed no favorable enthalpy change upon testing revealed that 10C9 rigorously identifies their cyclic structure and a characteristic hydroxyl group. In summary, this study demonstrates that enthalpy change is an effective index for ligand-design studies.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 129 (11), 1311-1317, 2009-11-01

    公益社団法人 日本薬学会

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