Enthalpy-Entropy Trade-Off Underlies Geometric Isomer Selectivity in Histamine H₁ Receptor-Doxepin Interaction.

Area of Science:

• Pharmacology
• Biophysics
• Computational Chemistry

Background:

• G-protein-coupled receptors (GPCRs) are critical drug targets.
• Understanding ligand binding thermodynamics is key for rational drug design.
• Histamine H1 receptor (H1R) plays a role in allergic responses.

Purpose of the Study:

• To investigate the thermodynamic basis of H1R's recognition of doxepin geometric isomers.
• To elucidate the role of conformational restriction and flexibility in GPCR-ligand interactions.
• To provide mechanistic insights into enthalpy-entropy trade-offs in drug binding.

Main Methods:

• Isothermal titration calorimetry (ITC) to measure binding thermodynamics.
• Molecular dynamics (MD) simulations to analyze ligand-receptor interactions.
• Cluster analysis of MD trajectories to assess conformational changes.

Main Results:

• The Z-isomer of doxepin showed greater enthalpic gain and entropic loss compared to the E-isomer at H1R.
• Mutating T1123.37V diminished these thermodynamic differences.
• MD simulations indicated Z-doxepin adopts a more restricted conformation upon binding.
• Distinct thermodynamic fingerprints differentiate E- and Z-doxepin binding to H1R.

Conclusions:

• H1R differentiates between doxepin isomers via distinct thermodynamic signatures.
• Conformational restriction influences the enthalpy-entropy balance in ligand binding.
• Findings guide the design of GPCR ligands with optimized thermodynamic and functional properties.