Physicochemical QSAR Analysis of Passive Permeability Across Caco-2 Monolayers

Area of Science:

• Pharmacology and Drug Discovery
• Biophysical Chemistry
• Computational Biology

Background:

• Caco-2 cell monolayers are a standard in vitro model for predicting intestinal drug absorption.
• Understanding passive diffusion across the intestinal epithelium is crucial for drug development.
• Existing models often lack mechanistic detail or broad applicability.

Purpose of the Study:

• To develop and validate a mechanistic in silico model for predicting Caco-2 cell permeability (P_e).
• To correlate physicochemical properties with drug permeation rates.
• To provide a tool for optimizing drug candidates for oral absorption.

Main Methods:

• Compiled a database of 1366 Caco-2 P_e values for 768 compounds.
• Employed multistep nonlinear regression analysis.
• Incorporated hydrodynamic, transcellular diffusion, and unstirred water layer components into the model.

Main Results:

• The developed model accurately predicts log P_e with a residual mean square error <0.5 log units.
• The model integrates size, charge, lipophilicity (log D), pKa, and hydrogen bonding potential.
• Mechanistic components explained variations in permeability across different experimental conditions.

Conclusions:

• The proposed model offers a robust and interpretable method for predicting intestinal drug absorption.
• It serves as a valuable tool in early-stage drug discovery to identify compounds with favorable absorption profiles.
• Physicochemical properties are key determinants of passive diffusion across the Caco-2 barrier.