Development of an Interpretable QSAR Model for Predicting Coagulation Factor XIIa Inhibitors Using Ensemble Machine Learning

Background/Objective: Activated coagulation factor XII (FXIIa) is a component of the contact activation pathway and a pharmacologically relevant target in contact-system-associated processes. In this study, scaffold-aware and interpretable machine-learning QSAR models were developed for human FXIIa activity. Methods: Bioactivity records for the human single protein target CHEMBL2821 were retrieved from ChEMBL release 37. Modeling was restricted to exact IC50 measurements from assays explicitly referring to FXIIa, Factor XIIa, or activated Factor XII. Median-consolidated pIC50 values and two-dimensional Mordred descriptors were evaluated using leakage-safe preprocessing, scaffold-disjoint validation, Y-randomization, applicability domain analysis, structural similarity auditing, and SHAP interpretation. Results: The regression dataset comprised 424 compounds and 166 Bemis–Murcko scaffolds in this study. The Gradient Boosting regressor achieved R² = 0.7560, RMSE = 0.6924, and MAE = 0.4965 on the locked scaffold-disjoint test set (n = 85); across 50 repeated scaffold partitions, the mean R² was 0.6892 ± 0.1515. The classification model achieved ROC-AUC = 0.9453, PR-AUC = 0.9807, balanced accuracy = 0.7561, and MCC = 0.5972 (n = 73). Y-randomization supported nonrandom predictive signals (empirical p = 0.0099). Conclusions: The models support computational prioritization within the represented FXIIa chemical domain, while prospective evaluation of independently generated compounds remains necessary.