title: [Rational fragment-design method based on a thermodynamic analysis].
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.
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan. tsumoto@k.u-tokyo.ac.jp
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
authors.forename: Mihoko
authors.initials: M
authors.lastname: Ui
mesh_terms: D000906:Antibodies; D000937:Antigen-Antibody Reactions; D002922:Ciguatoxins / Q000276:immunology; D055808:Drug Discovery / Q000379:methods*; D008024:Ligands; D011506:Proteins; D013816:Thermodynamics
chemical_list: D000906:Antibodies; D008024:Ligands; D011506:Proteins; D002922:Ciguatoxins