LiSENCE: A Hybrid Ligand and Sequence Encoder Network for Predicting CYP450 Inhibitors in Safe Multidrug Administration

Adverse drug–drug interactions (DDIs) often arise from cytochrome P450 (CYP450) enzyme inhibition, which is vital for metabolism. The accurate identification of CYP450 inhibitors is crucial, but current machine learning models struggle to assess the importance of key inputs like ligand SMILES and protein sequences, limiting their biological insights. The proposed study developed LiSENCE, an artificial intelligence (AI) framework to identify CYP450 inhibitors. It aimed to enhance prediction accuracy and provide biological insights, improving drug development and patient safety regarding drug–drug interactions: The innovative LiSENCE AI framework comprised four modules: the Ligand Encoder Network (LEN), Sequence Encoder Network (SEN), classification module, and explainability (XAI) module. The LEN and SEN, as deep learning pipelines, extract high-level features from drug ligand strings and CYP protein target sequences, respectively. These features are combined to improve prediction performance, with the XAI module providing biological interpretations. Data were outsourced from three databases: ligand/compound SMILES strings from the PubChem and ChEMBL databases and protein target sequences from the Protein Data Bank (PDB) for five CYP isoforms: 1A2, 2C9, 2C19, 2D6, and 3A4. The model attains an average accuracy of 89.2%, with the LEN and SEN contributing 70.1% and 63.3%, respectively. The evaluation performance records 97.0% AUC, 97.3% specificity, 92.2% sensitivity, 93.8% precision, 83.3% F1-score, and 87.8% MCC. LiSENCE outperforms baseline models in identifying inhibitors, offering valuable interpretability through heatmap analysis, which aids in advancing drug development research.