Rational fragment-design method based on a thermodynamic analysis

Kouhei Tsumoto, Mihoko Ui

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1311-1317
Number of pages7
JournalYakugaku Zasshi
Volume129
Issue number11
DOIs
Publication statusPublished - 2009 Nov

Keywords

  • Antibody
  • Ciguatoxin
  • Ligand design
  • Thermodynamic analysis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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