An Approach to Rational Ligand-Design Based on a Thermodynamic Analysis

Mihoko      Ui; Kouhei      Tsumoto

doi:10.2174/187220810793611482

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.

Keywords: Thermodynamic analysis, fragment design, ligand screening, isothermal titration calorimetry (ITC), Ciguatoxin, antibody, homeostatic mechanism, molecular biology, screening methods, Structure-Based Drug Design (SBDD), Fragment-Based Drug Discovery (FBDD), Isothermal-titration, biomolecular interactions, enthalpy, stoichiometry, non-covalent bonds, hydration, thermal mobility, protein-ligand interactions, hydrophobic interaction, water-insoluble, van der Waals interactions, lead compound, high affinity, anti-ciguatoxin anti-body, target protein, optimization, polycyclic ethers, exothermic reactions, phosphate buffered saline, aromaticity, carbonyl group, hydroxyl group