Problematic Attributions of Entropic and Hydrophobic Effects in Drug Interactions

Area of Science:

• Chemical Biology
• Drug Discovery
• Supramolecular Chemistry

Background:

• Drug affinity and noncovalent interactions with biopolymers are crucial for drug discovery.
• Supramolecular complexes offer a method to identify, quantify, and understand specific interactions and their medium dependence.
• Accurate prediction of entropic contributions (TΔS) to binding free energy (ΔG) remains challenging, especially in drug associations.

Purpose of the Study:

• To clarify the nature of hydrophobic effects in intermolecular associations.
• To quantify dispersive binding contributions using supramolecular porphyrin complexes.
• To explore the utility of binding contribution data for artificial intelligence in drug discovery.

Main Methods:

• Design and utilization of supramolecular complexes for interaction analysis.
• Measurement of binding contributions, including van der Waals and dispersive forces.
• Correlation analysis of binding contributions with molecular properties like polarizability.

Main Results:

• Hydrophobic effects in some drug complexes are primarily due to van der Waals or dispersive interactions, not solely hydrophobicity.
• Dispersive binding contributions derived from supramolecular complexes correlate with molecular polarizability.
• Heteroatoms and π-systems enhance van der Waals contributions, contrary to typical hydrophobic effect expectations.

Conclusions:

• Supramolecular complex measurements provide valuable data on dispersive binding forces.
• This data can refine our understanding of noncovalent interactions in drug discovery.
• Future applications include expanding AI-driven drug discovery databases with specific binding contribution data.