# Toward a Mechanistic Framework for Intestinal Drug Permeability: Integrating In Silico Modeling with Biorelevant Assays

## TL;DR

This paper proposes a new framework combining computer models and experiments to better understand how drugs pass through the intestine.

## Contribution

The novel contribution is an integrated framework combining MD modeling with biorelevant assays to improve drug permeability predictions.

## Key findings

- Traditional models lack mechanistic insight, limiting their predictive power.
- Combining MD simulations with experimental validation provides deeper mechanistic understanding.
- The framework resolves discrepancies between predicted and actual drug permeability.

## Abstract

Predicting oral bioavailability remains a central challenge
in
pharmaceutical sciences, primarily limited by the phenomenological
nature of traditional predictive models that provide correlations
without mechanistic insight. While molecular dynamics (MD) simulations
provide detailed atomistic insights into drug-membrane interactions,
they require rigorous experimental validation. Conversely, biorelevant
assayssuch as Caco-2 monolayers and everted gut sacssupply
essential biological end points but with limited mechanistic granularity.
This review systematically evaluates the strengths and limitations
of disparate approaches, from static quantitative structure–property
relationship (QSAR) models to physics-based molecular simulations.
We propose an integrated framework that synergistically combines the
physical resolution of multiscale MD modeling with the biological
relevance of hierarchical experimental validation. Using a representative
molecule with a divergent pharmacokinetic profilecharacterized
by high predicted permeability yet substantial metabolic instabilityas
an exemplary case, we present a mechanistic workflow for resolving
such discrepancies. This integrated approach transforms the validation
process from a binary outcome into a diagnostic tool for mechanistic
deconstruction, ultimately guiding the rational design of next-generation
orally bioavailable therapeutics.