Evaluating the correlation of binding affinities between isothermal titration calorimetry and fragment molecular orbital method of estrogen receptor beta with diarylpropionitrile (DPN) or DPN derivatives

Estrogen receptors (ERs) are ligand-activated transcription factors, with two subtypes ER alpha and ER beta. The endogenous ligand of ERs is the common 17 beta-estradiol, and the ligand-binding pocket of ER alpha and ER beta is very similar. Nevertheless, some ER beta-selective agonist ligands have been reported. DPN (diarylpropionitrile) is a widely used ER beta-selective agonist; however, the structure of the ER beta-DPN complex has not been solved. Therefore, the bound-state conformation of DPN and its enantioselectivity remain unresolved. In this report, we present the structures of the complexes of ER beta with DPN or its derivatives that include a chlorine atom by the Xray crystallography. Additionally, we measured the binding affinity between ER beta and DPN or derivatives by isothermal titration calorimetry (ITC) and estimated the binding affinity by fragment molecular orbital (FMO) calculations. We also examined the correlation between the ITC data and results from the FMO calculations. FMO calculations showed that S-DPN interacts strongly with three amino acids (Glu305, Phe356, and His475) of ER beta, and ITC measurements confirmed that the chlorine atom of the DPN derivatives enhances binding affinity. The enthalpy change by ITC correlated strongly with the interaction energy (total IFIEs; inter-fragment interaction energies) calculated by FMO (R = 0.870). We propose that FMO calculations are a valuable approach for enhancing enthalpy contributions in drug design, and its scope of applications includes halogen atoms such as chlorine. This study is the first quantitative comparison of thermodynamic parameters obtained from ITC measurements and FMO calculations, providing new insights for future precise drug design.

Automated summary

This study examines the binding mode and interaction between ERβ and DPN or its derivatives using X-ray crystallography, isothermal titration calorimetry (ITC), and fragment molecular orbital (FMO) calculations. The results show that the chlorine atom in DPN derivatives enhances binding affinity, and FMO calculations are valuable for enhancing enthalpy contributions in drug design.