Thermodynamic and Extra-Thermodynamic Investigations of Bioactive Compounds With Endothelin A Receptor by Nonlinear...

Understanding the thermodynamic and extra-thermodynamic interactions of a ligand to its target can provide important insights into ligand affinity and efficiency. Using endothelin receptor A (ET_AR) as an example, ET_AR was immobilized on ibrutinib-modified silica gels to prepare affinity stationary phase. After specificity and stability characterization, the affinity column was utilized to investigate the interactions between four ligands with ET_AR. The four ligands were ambrisentan, paeoniflorin (PAE), ferulic acid (FA), and salvianolic acid B (SAB). Nonlinear chromatography was applied to determine the affinities of the ligands with ET_AR at temperature range of 283.15~318.15 K. Entropy change (ΔH), enthalpy change (ΔS), and Gibbs free energy change (ΔG) were determined. The ΔH and ΔS remain constant for ambrisentan and PAE. While enthalpy-entropy compensation happened for FA and SAB, indicating conformational changes occurred during the binding of them with ET_AR. PAE had similar thermodynamic behaviors to ambrisentan (an approved drug targeting ET_AR for the treatment of pulmonary arterial hypertension), implying that the ligand has greater possibilities to be a lead than FA and SAB. This result was also confirmed by a survey of DrugBank. Together, the method may become an alternative for predicting the druglike property of a newly discovered bioactive compound.