title: An approach to rational ligand-design based on a thermodynamic analysis.
abstract: 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.
authors.affiliation: Graduate School of Frontier Sciences, The University of Tokyo, Japan.
authors.forename: Mihoko
authors.initials: M
authors.lastname: Ui
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
mesh_terms: D000906:Antibodies / Q000378:metabolism; D000937:Antigen-Antibody Reactions; D001665:Binding Sites; D002151:Calorimetry; D002922:Ciguatoxins / Q000737:chemistry* / Q000276:immunology; D019277:Entropy; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D013816:Thermodynamics
chemical_list: D000906:Antibodies; D008024:Ligands; D002922:Ciguatoxins