An approach to rational ligand-design based on a thermodynamic analysis

Mihoko Ui, Kouhei Tsumoto

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Thermodynamic analysis is an effective tool in screening of lead-compounds for development of potential drug candidates. In most cases, a ligand achieve high affinity and specificity to a target protein by means of both favorable enthalpy and entropy terms, which can be reflected in binding profiles of Isothermal Titration Calorimetry (ITC). A favorable enthalpy change suggests the contribution of noncovalent contacts such as hydrogen bonding and van der Waals interaction between a ligand and its target protein. In general, optimization of binding enthalpy is more difficult than that of entropies in ligand-design; therefore, it is desirable to choose firstly a lead-compound based on its binding enthalpic gain. In this paper, we demonstrate the utility of thermodynamic approach to ligand screening using anti-ciguatoxin antibody 10C9 as a model of a target protein which possesses a large hydrophobic pocket. As a result of this screening, we have identified three compounds that could bind to the antigen-binding pocket of 10C9 with a few kcal/mol of favorable binding enthalpy. Comparison of their structure with the proper antigen ciguatoxin CTX3C revealed that 10C9 rigorously identifies their cyclic structure and a characteristic hydroxyl group. ITC measurement might be useful and powerful for a rational ligand screening and the optimization of the ligand; the enthalpic gain is an effective index for ligand-design studies.

Original languageEnglish
Pages (from-to)183-188
Number of pages6
JournalRecent Patents on Biotechnology
Issue number3
Publication statusPublished - 2010


  • Antibody
  • Ciguatoxin
  • Fragment design
  • Isothermal titration calorimetry (itc)
  • Ligand screening
  • Thermodynamic analysis


Dive into the research topics of 'An approach to rational ligand-design based on a thermodynamic analysis'. Together they form a unique fingerprint.

Cite this