Prediction of Passive Membrane Permeability by Semi-Empirical Method Considering Viscous and Inertial Resistances and Different Rates of Conformational Change and Diffusion.

Yoshifumi Fukunishi,Koh Takeuchi,Takashi Kurosawa,Yoshinori Wakabayashi,Tadaaki Mashimo,Hironori K Nakamura

doi:10.1002/minf.201900071

Abstract

Membrane permeability is an important property of drugs in adsorption. Many prediction methods work well for small molecules, but the prediction of middle‐molecule permeability is still difficult. In the present study, we modified a classical permeability model based on Fick's law to study passive membrane permeability. The model consisted of the distribution of solute from water to membrane and the diffusion of solute in each solvent. The diffusion coefficient is the inverse of the resistance, and we examined the inertial resistance in addition to the viscous resistance, the latter of which has been widely used in permeability prediction. Also, we examined three models changing the balance between the diffusion of solute in membrane and the conformational change of solute. The inertial resistance improved the prediction results in addition to the viscous resistance. The models worked well not only for small molecules but also for middle molecules, whose structures have more conformational freedom.

Highlights

It is still one of the hot topics, especially under circumstances where the molecular weights of drug molecules have been increasing and larger molecules often face the lower permeability than smaller drug molecules do
We proposed a quantitative structure-property relationship (QSPR) method for for evaluating the apparent membrane permeability (Papp) based on an analysis of the diffusion process and the partition function calculation with conformer sampling
The molecular descriptors were calculated based on the structural ensemble of the solute

Summary

Introduction

Permeability is one of the most important factors in a drug’s adsorption and target-binding properties in cells. The understanding and predicting membrane permeability of molecules have been studied for last few decades. The main permeability problems are adsorption in human intestine, extraction from kidney, penetration of the blood-brain barrier, skin permeability, and the permeability of the cell membrane to approach target proteins in cells. Caco-2 cells and MDCK cell systems are two of the model systems that mimic human intestine adsorption and extraction from kidney, respectively. Solute molecules penetrate the cell membrane by diffusion (transcellular), the solute molecules go through the tight junction (paracellular), and transporters and channel proteins work in the influx and efflux processes. Among these mechanisms, PAMPA permeability represents transcellular passive permeability

Methods

Results

Conclusion