NeSyDPP4-QSAR: A Neuro-Symbolic AI Approach for Potent DPP-4-Inhibitor Discovery in Diabetes Treatment

Abstract

Diabetes Mellitus (DM) is a global epidemic and among the top ten leading causes of mortality (WHO, 2019), projected to rank seventh by 2030. The US National Diabetes Statistics Report (2021) states that 38.4 million Americans have diabetes. Dipeptidyl Peptidase-4 (DPP-4) is an FDA-approved target for type 2 diabetes mellitus (T2DM) treatment. However, current DPP-4 inhibitors are associated with adverse effects, including gastrointestinal issues, severe joint pain (FDA safety warning), nasopharyngitis, hypersensitivity, and nausea. Identifying novel inhibitors is crucial. Direct in vivo DPP-4 inhibition assessment is costly and impractical, making in silico IC50 prediction a viable alternative. Quantitative Structure-Activity Relationship (QSAR) modeling is a widely used computational approach for chemical substance assessment. We employ LTN, a neuro-symbolic approach, alongside DNN and transformers as baselines. DPP-4-related data is sourced from PubChem, ChEMBL, BindingDB, and GTP, comprising 6,563 bioactivity records (SMILES-based compounds with IC50 values) after deduplication and thresholding. A diverse set of features including descriptors (CDK Extended-PaDEL), fingerprints (Morgan), chemical language model embeddings (ChemBERTa2), LLaMa 3.2, and physicochemical properties is used to train the NeSyDPP4-QSAR model. The NeSyDPP4-QSAR model yielded the highest accuracy, incorporating CDKextended and Morgan fingerprints, with an accuracy of 0.9725, an F1-score of 0.9723, an ROC AUC of 0.9719, and an MCC of 0.9446. The performance was benchmarked against two standard baseline models: a deep neural network and a transformer. To ensure fair comparisons, DNN models used the equivalent attributes with the same dimension and network configuration as NeSyDPP4-QSAR. Our findings showed that integrating the Neuro-symbolic strategy (neural network-based learning and symbolic reasoning) holds immense potential for discovering drugs that can inhibit diabetes mellitus and classifying biological activities that inhibit it.