Artificial Intelligence-Based Quantitative Structure–Property Relationship Model for Predicting Human Intestinal Absorption of Compounds with Serotonergic Activity

[Image: see text] Oral medicines represent the largest pharmaceutical market area. To achieve a therapeutic effect, a drug must penetrate the intestinal walls, the main absorption site for orally delivered active pharmaceutical ingredients (APIs). Indeed, predicting drug absorption can facilitate candidate screening and reduce time to market. Algorithms are available with good prediction accuracy that however focus only on solubility. In this work, we focused on drug permeability looking at human intestinal absorption as a marker for intestinal bioavailability. Being of considerable therapeutic relevance, APIs with serotonergic activity were selected as a dataset. Due to process complexity, experimental data scarcity, and variability, we turned toward an artificial intelligence (AI)-based system, which is a hierarchical combination of classification and regression models. This combination of seemingly two models into a single system widens the space of molecules classified as highly permeable with high accuracy. The specialized and optimized system enables in silico and structure-based prediction with a high degree of certainty. Predictions in external validation allowed correct selection of the 38% of highly permeable molecules without any false positives. The proposed system based on AI represents a promising tool useful for oral drug screening at an early stage of drug discovery and development. Datasets and the obtained models are available on the GitHub platform (https://github.com/nczub/HIA_5-HT).