Explainable Artificial Intelligence in Drug Discovery: Bridging Predictive Power and Mechanistic Insight

ABSTRACT Explainable artificial intelligence (XAI) is increasingly essential in drug discovery, where interpretability and trust must accompany predictive accuracy. As deep learning models, particularly, deep neural networks (DNNs) and graph neural networks (GNNs), enhance molecular property prediction, de novo design, and toxicity estimation, transparent, mechanistically meaningful insights become critical. This article classifies major XAI strategies in computational molecular science, including gradient‐based attribution, perturbation analysis, surrogate modeling, counterfactual reasoning, and self‐explaining architectures. Molecular representations, such as fingerprints, SMILES, molecular graphs, and latent embeddings, are evaluated for their impact on explanation fidelity. An evaluation framework is outlined using metrics like fidelity, stability, completeness, sparsity, and usability, with emphasis on integration into drug discovery workflows. The discussion also highlights emerging directions, including neuro‐symbolic systems and physics‐informed networks that embed mechanistic constraints into statistical models. By aligning algorithmic transparency with pharmacological reasoning, XAI not only demystifies black‐box models but also supports scientific insight, regulatory compliance, and ethical AI deployment in pharmaceutical research. This article is categorized under: Data Science > Artificial Intelligence/Machine Learning Data Science > Chemoinformatics Structure and Mechanism > Computational Biochemistry and Biophysics