What question did this study set out to answer?

To develop and validate a hierarchical virtual screening framework for identifying IDO1 inhibitors effectively.

June 1, 2026Open Access

A Reproducible Hierarchical Virtual Screening Framework Integrating Scaffold-Aware Machine Learning, Ensemble Docking, and Molecular Dynamics: Application to IDO1

Puntos clave

To develop and validate a hierarchical virtual screening framework for identifying IDO1 inhibitors effectively.
Integrated scaffold-aware machine learning, ensemble docking, and molecular dynamics simulations.
Used a curated ChEMBL data set with strict standardization and activity binarization.
Models were trained using Random Forest, XGBoost, and SVM classifiers with cross-validation to ensure reliability.
Achieved ROC-AUC of ≈0.88-0.89 for predictive performance.
Identified 39 FDA-approved compounds predicted as active against IDO1.
Top candidates displayed stable binding modes in 300 ns molecular dynamics simulations with key catalytic residues.

Resumen

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme implicated in cancer immune escape and remains an attractive therapeutic target despite recent clinical setbacks. We report a fully reproducible hierarchical virtual screening framework integrating scaffold-aware machine learning, ensemble docking, consensus scoring, and molecular dynamics simulations for robust prioritization of IDO1 inhibitors. A curated ChEMBL data set of IDO1 inhibitors was subjected to strict standardization, duplicate removal, and activity binarization at pChEMBL ≥6. Models were trained using scaffold-based splitting and nested cross-validation to prevent chemical series leakage. An ensemble of Random Forest, XGBoost and SVM classifiers achieved balanced predictive performance (ROC-AUC ≈0.88-0.89) with applicability domain filtering to ensure reliability. Prospective screening of FDA-approved drugs yielded 39 compounds within the applicability domain predicted as active. These were further evaluated through ensemble docking against multiple IDO1 crystal structures using GNINA with CNN rescoring. Consensus strategies were systematically benchmarked, demonstrating that best-Z-score aggregation outperformed mean, rank-based, and weighted methods in enrichment factor (EF) metrics. Two top-ranked candidates were subjected to 300 ns molecular dynamics simulations, revealing stable binding modes and persistent interactions with key catalytic residues. This study demonstrates that hierarchical integration of scaffold-aware machine learning with structure-based ensemble strategies enhances robustness and reduces false positives in virtual screening campaigns. The proposed workflow is generalizable and supports reproducible candidate prioritization in computational drug discovery. The complete implementation, including data processing, model training, and analysis steps, is provided as a fully executable Jupyter notebook available at https://github.com/rocco-b/IDO1-inhibitors-ML-and-docking-data.

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Cite This Study

Tomarchio et al. (Fri,) studied this question.

synapsesocial.com/papers/6a1d21e502fbce9130637bfb https://doi.org/https://doi.org/10.1021/acs.jcim.6c00967

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