Understanding drug solubilization in intestinal mixed micelles through molecular dynamics simulations

Area of Science:

• Pharmaceutical Sciences
• Computational Chemistry
• Physical Chemistry

Background:

• Solubilization is key in pharmaceutical and chemical industries, but molecular-level understanding of solubilized molecules within micelles remains limited.
• Predicting solubilization in silico is a significant challenge due to complex interactions.
• All-atom molecular dynamics simulations offer a promising approach to elucidate these interactions.

Purpose of the Study:

• To improve molecular-level understanding of drug solubilization within intestinal mixed micelles.
• To enable in silico prediction of drug solubilization using molecular dynamics simulations.
• To investigate the location, orientation, and interactions of solubilized drugs.

Main Methods:

• Simulated solubilization of six drugs in mixed micelles (taurocholate and dioleoyl phosphatidylcholine) using all-atom molecular dynamics in explicit water.
• Experimentally measured solubilization using liquid chromatography.
• Analyzed drug location and orientation via cumulative radial distribution functions and interactions using radial distribution function ratios and hydrogen bonding.

Main Results:

• Developed a novel simulation-derived parameter correlating drug-micelle and drug-water interactions with experimental solubilization (R² = 0.83).
• Lipophilicity determined drug location within micelles (core, palisade, or surface).
• Hydrogen bonding significantly influenced the orientation and solubilization of specific drugs.

Conclusions:

• Explicit, hydrogen bond-forming water molecules are essential for accurate solubilization prediction.
• The study provides a robust framework for quantitative analysis of drug location and orientation in micelles.
• Molecular dynamics simulations are valuable tools for predicting and understanding drug solubilization processes.