CliffRank: A Dual-Branch Framework for Activity-Cliff Ranking Prediction

Activity-cliff ranking remains difficult because local structural changes can cause large activity differences, while high-quality data that resolve the underlying mechanisms remain limited. To use available activity labels more effectively, we combine absolute-activity regression with ranking-consistency learning. CliffRank trains two parallel predictors with mean squared error, a thresholded listwise loss, and Pairwise Preference Consistency (PPC), which aligns relative ordering in the preference-probability space. On three antimicrobial peptide datasets, CliffRank with ESM2-t12 achieved the highest mean Spearman correlation of 0.5393 and mean Recall@50 of 21.4, although the leading method varied across individual datasets. On three small-molecule datasets, CliffRank with PNA, where PPC was activated after 120 epochs, achieved the highest mean Spearman correlation of 0.6890, while its mean Recall@50 of 30.4 matched that of ACANet-PNA. The PPC results also define its practical limits. Asymmetric initialization improved the MolCLR-GIN averages but did not improve every target. For PNA without pretrained weights, delayed PPC improved selected metrics, but no schedule was best for both mean Spearman correlation and mean Recall@50. Future work should evaluate more targets and antimicrobial peptide systems, develop adaptive PPC schedules, and incorporate protein or membrane context when available.

QBioFusion-QSAR: Morgan-Anchored Quantum Multiple Kernel Learning for Small-Data Ligand Classification

Small quantitative structure-activity relationship (QSAR) studies are difficult when close molecular analogues have different activity labels. This paper asks whether a quantum kernel can add similarity information to a Morgan/Tanimoto fingerprint model, and which molecules account for the change. QBioFusion-QSAR uses quantum multiple kernel learning (QMKL): a support vector machine combines a Morgan/Tanimoto kernel with a quantum fidelity kernel constructed from fold-local components derived from RDKit and Mordred descriptors and Deep-PK features. Linear and radial basis function descriptor kernels are included as classical controls. On the 54-molecule PsychLight-A benchmark, Morgan/Tanimoto was the strongest single representation. In the primary stratified five-fold evaluation, QMKL increased accuracy from 0.815 to 0.833 and Matthews correlation coefficient (MCC) from 0.613 to 0.645. Matched-regularization auditing attributed the change to N-Me-5-HT and N-Me-tryptamine changing from false-negative to true-positive predictions; activity-cliff subset MCC increased from 0.07 to 0.22. Repeating the five-fold protocol over ten random partitionings showed that learned QMKL did not exceed Morgan/Tanimoto on mean MCC; paired held-out bootstrap intervals for the matched comparison also span zero. These results support QBioFusion-QSAR as an auditable QMKL framework for identifying localized residual quantum-kernel contributions in small-data, activity-cliff-aware ligand classification.